Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

This application claims priority to U.S. Patent Application Ser. No.61/317,575, filed on Mar. 25, 2010, and is incorporated herein byreference by its entirety.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity of Bcl-2anti-apoptotic proteins, compositions containing the compounds, andmethods of treating diseases during which anti-apoptotic Bcl-2 proteinsare expressed.

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 proteins are associated with a number of diseases.There is therefore an existing need in the therapeutic arts forcompounds which inhibit the activity of anti-apoptotic Bcl-2 proteins.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, spleen cancer, and the like is described incommonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCTUS 2004/37911, published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmunc diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

SUMMARY OF THE INVENTION

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds chosen from

-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{benzoyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(phenylacetyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino    biphenyl-4-carboxamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;-   4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(1-methyl-2-oxo-3-azabicyclo[3.1.1]hept-3-yl)phertyl]sulfonyl}benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]hept-2-yl]amino}benzyl)piperazin-1-yl]benzamide;-   4-[4-(2-{[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[(1R,5R)-2-(4-chlorophenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl]methyl}piperazin-1-yl)-N-({-4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(2-{[adamantan-2-ylmethyl]amino}-5,5-dimethylcyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5,5-dimethyl-2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}cyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)-5-nitrobenzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{2-[2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   1-[adamantan-1-yl]-4-{2-[(4-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;-   4-(4-{2-[2-(adamantan-1-yl)-6-methylimidazo[1,2-a]pyridin-8-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-(adamantan-2-yl)-6-methyl-8-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}imidazo[1,2-a]pyridine-2-carboxamide;-   4-(4-{2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;-   N-cyclooctyl-5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-2-furamide;-   N-benzyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzyl)piperazin-1-yl]benzamide;-   4-(4-{2-[3-azabicyclo[3.2.2]non-3-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[tricyclo[4.3.1.1³,⁸]undec-4-en-4-yl]benzyl}piperazin-1-yl)benzamide;-   7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-phenylbicyclo    [2.2.1]hept-2-ene-1-carboxamide;-   7,7-dimethyl-2-{2-[(4-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   N-(adamantan-1-ylmethyl)-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   N-cyclopropyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   7,7-dimethyl-2-{2-[(4-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxylic;-   4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{4-[adamantan-2-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{1S,5S)-3-[adamantan-1-ylcarbonyl]-3,6-diazabicyclo[3.2.0]hept-6-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   6-{3-[adamantan-1-yl]-4-hydroxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;-   4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{[adamantan-2-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{2-[adamantan-1-yl]ethoxy}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   N³-[adamantan-1-ylacetyl]-N³-benzyl-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-beta-alaninamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamide;-   4-{4-[adamantan-1-yl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[3,5-dimethyladamantan-1-yl]piperazin-1-yl}benzamide;-   [(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b4′,5′-d]pyran-3a-yl]methyl;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;-   4-(4-{2-[adamantan-1-yl]ethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;-   N-({-4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-({(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)biphenyl-4-carboxamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzyl}piperazin-1-yl)benzamide;-   4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-(2-phenyl-1,3-benzoxazol-5-yl)-2-furamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(triphenylvinyl)benzyl]piperazin-1-yl}benzamide;-   4-{4-[2-(5-methyl-5,6-dihydrophenanthridin-6-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazin-1-yl}benzamide;-   4-(4-{2-[2-(2,6-dimethoxybenzoyl)-3-thienyl]benzylidene}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   1-[adamantan-1-yl]-4-{2-[(1-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperidin-4-ylidene)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzamide;-   4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;-   4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzylidene}piperidin-1-yl)benzamide;-   N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-oxo-4H-chromen-6-yl)benzamide;-   N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(1-octyl-1H-pyrazol-4-yl)benzamide;-   4-[5-(4-{[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenyl)-1,3-benzothiazol-2-yl]butanoic;-   N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-[(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]oct-3-yl]benzamide;-   6-{3-[adamantan-1-yl]-4-methoxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;-   4-{4-[adamantan-1-ylacetyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{[adamantan-1-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   N-{1-[4-({[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}carbamoyl)phenyl]piperidin-4-yl}adamantane-1-carboxamide;-   4-[adamantan-2-ylamino]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;    and-   N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}benzamide.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of acompound of this invention.

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount of acompound of this invention.

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of acompound of this invention and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, that monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C_(x)-C_(y) alkyl” meansa straight or branched hydrocarbon chain containing at least onecarbon-carbon double bond containing x to y carbon atoms. The term“C₂-C₄ alkenyl” means an alkenyl group containing 2-4 carbon atoms.Representative examples of alkenyl include, but are not limited tobuta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. The term “C_(x)-C_(y) alkylene” means a adivalent group derived from a straight or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and containing x to ycarbon atoms. Representative examples of alkenylene include, but are notlimited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term“C_(x)—C_(y) alkyl” means a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₁₀ alkyl”means a straight or branched chain, saturated hydrocarbon containing 2to 10 carbon atoms. Examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched, saturated hydrocarbon chain of 1 to 10 carbon atoms, forexample, of 1 to 4 carbon atoms. The term “C_(x)—C_(y) alkylene” means adivalent group derived from a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₆ alkylene”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Examples of alkylene include, but are not limited to,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. The term “C_(x)-C_(y) alkynyl”means a straight or branched chain hydrocarbon group containing from xto y carbon atoms. Representative examples of alkynyl include, but arenot limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

The term “alkynylene,” as used herein, means a divalent radical derivedfrom a straight or branched chain hydrocarbon group containing from 2 to10 carbon atoms and containing at least one carbon-carbon triple bond.

The term “aryl” as used herein, means phenyl.

The term “cyclic moiety,” as used herein, means benzene, phenyl,phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane,heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and spiroalkyl.

The term “cycloalkylene” or cycloalkyl” or “cycloalkane” as used herein,means a monocyclic or bridged hydrocarbon ring system. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or twoalkylene bridges, each consisting of one, two, or three carbon atoms,each linking two non-adjacent carbon atoms of the ring system.Non-limiting examples of such bridged cycloalkyl ring systems includebicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane,tricyclo[3.3.1.0³,⁷]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1³,⁷]decane (adamantane). Themonocyclic and bridged cycloalkyl can be attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The term “cycloalkenylene,” or “cycloalkenyl” or “cycloalkene” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbonatoms and zero heteroatoms. The four-membered ring systems have onedouble bond, the five- or six-membered ring systems have one or twodouble bonds, and the seven- or eight-membered ring systems have one,two, or three double bonds. Representative examples of monocycliccycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Themonocyclic cycloalkenyl ring may contain one or two alkylene bridges,each consisting of one, two, or three carbon atoms, each linking twonon-adjacent carbon atoms of the ring system. Representative examples ofthe bicyclic cycloalkenyl groups include, but are not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “cycloalkyne,” or “cycloalkynyl,” or “cycloalkynylene,” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkynyl has eight or more carbon atoms, zeroheteroatoms, and one or more triple bonds. The monocyclic cycloalkynylring may contain one or two alkylene bridges, each consisting of one,two, or three carbon atoms, each linking two non-adjacent carbon atomsof the ring system. The monocyclic and bridged cycloalkynyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “heteroarene,” or “heteroaryl,” or “heteroarylene,” as usedherein, means a five-membered or six-membered aromatic ring having atleast one carbon atom and one or more than one independently selectednitrogen, oxygen or sulfur atom. The heteroarenes of this invention areconnected through any adjacent atoms in the ring, provided that propervalences are maintained. Representative examples of heteroaryl include,but are not limited to, furanyl (including, but not limited thereto,furan-2-yl), imidazolyl (including, but not limited thereto,1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyridinyl (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiazolyl, thienyl (including, but not limited thereto, thien-2-yl,thien-3-yl), triazolyl, and triazinyl.

The term “heterocycloalkane,” or “heterocycloalkyl,” or“heterocycloalkylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and zero double bonds. The monocyclic and bridgedheterocycloalkane are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkanegroups include, but arc not limited to, Representative examples ofheterocycloalkane groups include, but are not limited to, morpholinyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl,tetrahydrofuranyl, thiomorpholinyl, dioxanyl, tetrahydrothienyl,tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine,azepanyl, aziridinyl, diazepanyl, dithiolanyl, dithianyl,isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl, oxazolidinyl,pyrazolidinyl, tetrahydrothienyl, thiadiazolidinyl, thiazolidinyl,thiomorpholinyl, trithianyl, and trithianyl.

The term “heterocycloalkene,” or “heterocycloalkenyl,” or“heterocycloalkenylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and one or more double bonds. The monocyclic and bridgedheterocycloalkene are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkenegroups include, but are not limited to, tetrahydrooxocinyl,1,4,5,6-tetrahydropyridazinyl, 1,2,3,6-tetrahydropyridinyl,dihydropyranyl, imidazolinyl, isothiazolinyl, oxadiazolinyl,isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl,thiadiazolinyl, thiazolinyl, and thiopyranyl.

The term “phenylene,” as used herein, means a divalent radical formed byremoval of a hydrogen atom from phenyl.

The term “spiroalkyl,” as used herein, means alkylene, both ends ofwhich are attached to the same carbon atom and is exemplified byC₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl, C₅-spiroalkyl,C₆-spiroalkyl, C₇-spiroalkyl, C₈-spiroalkyl, C₉-spiroalkyl and the like.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl having oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CR₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term, “spirocyclo,” as used herein, means two substituents on thesame carbon atom, that, together with the carbon atom to which they areattached, form a cycloalkane, heterocycloalkane, cycloalkene, orheterocycloalkene ring.

The term “C₂-C₅-spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, and C₅-spiroalkyl.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkyl,” as used herein, means prop-1,3-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkyl,” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl,” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “NH protecting group,” as used herein, means a substituent thatprotects NH groups against undesirable reactions during syntheticprocedures. Examples of NH protecting groups include, but are notlimited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl,benzyloxycarbonyl, para-nitrobenzylcarbonyl,ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl,tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluencsulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means a substituentthat protects C(O)OH groups against undesirable reactions duringsynthetic procedures. Examples of C(O)OH protecting groups include, butare not limited to, methyl, ethyl, n-propyl, isopropyl,1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl,diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl,bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl,para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-tri chloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, means asubstituent that protects OH or SH groups against undesirable reactionsduring synthetic procedures. Examples of OH or SH protecting groupsinclude, but are not limited to, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tort-butyldiphenylsilyl,diphenylmethylsilyl, and tort-butylmethoxyphenylsilyl.

For a review of protecting groups in organic synthesis, see Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.,Wiley-Interscience: New York, 2006.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, in which the terms “R” and “S”are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.Compounds having asymmetrically substituted carbon atoms with equalamounts of R and S configurations are racemic at those carbon atoms.Atoms with an excess of one configuration over the other are assignedthe configuration present in the higher amount, preferably an excess ofabout 85%-90%, more preferably an excess of about 95%-99%, and stillmore preferably an excess greater than about 99%. Accordingly, thisinvention includes racemic mixtures, relative and absolutestereoisomers, and mixtures of relative and absolute stereoisomers.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties mayhave attached thereto prodrug-forming moieties. The prodrug-formingmoieties are removed by metabolic processes and release the compoundshaving the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugsare useful for adjusting such pharmacokinetic properties of thecompounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but arc not limited to ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵ S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCTpublications WO1997010223, WO2005099353, WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-2 inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeuterated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to Bcl-2 activity. Increasing the amountof an isotope present in a compound above its natural abundance iscalled enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al.,Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23%in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 25-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmcokinetic profile or efficacy relative to the non-istopiccompound.

Amides, Esters and Prodrugs

Prodrugs are derivatives of an active drug designed to ameliorate someidentified, undesirable physical or biological property. The physicalproperties are usually solubility (too much or not enough lipid oraqueous solubility) or stability related, while problematic biologicalproperties include too rapid metabolism or poor bioavailability whichitself may be related to a physicochemical property.

Prodrugs are usually prepared by: a) formation of ester, hemi esters,carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates,imines, Mannich bases, phosphates, phosphate esters, and enamines of theactive drug, b) functionalizing the drug with azo, glycoside, peptide,and ether functional groups, c) use of aminals, hemi-aminals, polymers,salts, complexes, phosphoramides, acetals, hemiacetals, and ketal formsof the drug. For example, see Andrejus Korolkovas's, “Essentials ofMedicinal Chemistry”, John Wiley-Interscience Publications, John Wileyand Sons, New York (1988), pp. 97-118, which is incorporated in itsentirety by reference herein.

Esters can be prepared from substrates of formula (I) containing eithera hydroxyl group or a carboxy group by general methods known to personsskilled in the art. The typical reactions of these compounds aresubstitutions replacing one of the heteroatoms by another atom, forexample:

Amides can be prepared from substrates of formula (I) containing eitheran amino group or a carboxy group in similar fashion. Esters can alsoreact with amines or ammonia to form amides.

Another way to make amides from compounds of formula (I) is to heatcarboxylic acids and amines together.

In Schemes 2 and 3 above, R and R′ are independently substrates offormula (I), alkyl or hydrogen.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds chosen from

-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{benzoyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(phenylacetyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;-   4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(1-methyl-2-oxo-3-azabicyclo[3.1.1]hept-3-yl)phenyl]sulfonyl}benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]hept-2-yl]amino}benzyl)piperazin-1-yl]benzamide;-   4-[4-(2-{[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[(1R,5R)-2-(4-chlorophenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl]methyl}piperazin-1-yl)-N-({-4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(2-{[adamantan-2-ylmethyl]amino}-5,5-dimethylcyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5,5-dimethyl-2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}cyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)-5-nitrobenzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{2-[2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   1-[adamantan-1-yl]-4-{2-[(4-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;-   4-(4-{2-[2-(adamantan-1-yl)-6-methylimidazo[1,2-a]pyridin-8-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-(adamantan-2-yl)-6-methyl-8-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}imidazo[1,2-a]pyridine-2-carboxamide;-   4-(4-{2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;-   N-cyclooctyl-5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-2-furamide;-   N-benzyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzyl)piperazin-1-yl]benzamide;-   4-(4-{2-[3-azabicyclo[3.2.2]non-3-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[tricyclo[4.3.1.1³,⁸]undec-4-en-4-yl]benzyl}piperazin-1-yl)benzamide;-   7,7-dimethyl-2-{2-[(4-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-phenylbicyclo    [2.2.1]hept-2-ene-1-carboxamide;-   7,7-dimethyl-2-{2-[(4-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   N-(adamantan-1-ylmethyl)-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   N-cyclopropyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;-   7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxylic;-   4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{4-[adamantan-2-ylcarbony]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{1S,5S)-3-[adamantan-1-ylcarbonyl]-3,6-diazabicyclo[3.2.0]hept-6-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   6-{3-[adamantan-1-yl]-4-hydroxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;-   4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{[adamantan-2-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{2-[adamantan-1-yl]ethoxy}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   N³-[adamantan-1-ylacetyl]-N³-benzyl-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-beta-alaninamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamide;-   4-{4-[adamantan-1-yl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[3,5-dimethyladamantan-1-yl]piperazin-1-yl}benzamide;-   [(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3    aH-bis[1,3]dioxolo[4,5-b4′,5′-d]pyran-3a-yl]methyl;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;-   4-(4-{2-[adamantan-1-yl]ethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;-   N-({-4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-({(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)biphenyl-4-carboxamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzyl}piperazin-1-yl)benzamide;-   4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-(2-phenyl-1,3-benzoxazol-5-yl)-2-furamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(triphenylvinyl)benzyl]piperazin-1-yl}benzamide;-   4-{4-[2-(5-methyl-5,6-dihydrophenanthridin-6-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazin-1-yl}benzamide;-   4-(4-{2-[2-(2,6-dimethoxybenzoyl)-3-thienyl]benzylidene}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   1-[adamantan-1-yl]-4-{2-[(1-{-4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperidin-4-ylidene)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzamide;-   4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;-   4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzylidene}piperidin-1-yl)benzamide;-   N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenypsulfonyl]-4-(4-oxo-4H-chromen-6-yl)benzamide;-   N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenypsulfonyl]-4-(1-octyl-1H-pyrazol-4-yl)benzamide;-   4-[5-(4-{[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}-phenyl)-1,3-benzothiazol-2-yl]butanoic;-   N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-[(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]oct-3-yl]benzamide;-   6-{3-[adamantan-1-yl]-4-methoxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;-   4-{4-[adamantan-1-ylacetyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-{[adamantan-1-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   N-{1-[4-({[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}carbamoyl)phenyl]piperidin-4-yl}adamantane-1-carboxamide;-   4-[adamantan-2-ylamino]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;    and-   N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}benzamide.

Pharmaceutical Compositions, Combination Therapies, Methods ofTreatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound of this invention and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound of this invention.

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound of this invention.

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-2 proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound of this invention.

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-2 proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound of this invention.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound of this invention.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myclogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound of this invention.

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-2 proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound of this invention and a therapeutically effectiveamount of one additional therapeutic agent or more than one additionaltherapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-2 proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound of this invention and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositionscomprising an excipient and a therapeutically effective amount of thecompound of this invention and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound of this invention and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds of this invention, produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-2 proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds of this invention may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-2 proteins.

Compounds of this invention may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds and prodrugs thereof are contemplated as being embraced bythis invention. Basic addition salts of the compounds are those derivedfrom the reaction of the compounds with the hydroxide, carbonate orbicarbonate of cations such as lithium, sodium, potassium, calcium, andmagnesium.

The compounds of this invention may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds of this invention dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this invention ofthis invention used to make a composition to be administered daily to apatient in a single dose or in divided doses is from about 0.03 to about200 mg/kg body weight. Single dose compositions contain these amounts ora combination of submultiples thereof.

Compounds of this invention may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound of thisinvention to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention to be administered ophthalmically or orally in liquid dosageforms include, for example, 1,3-butylene glycol, castor oil, corn oil,cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil,groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols,propylene glycol, sesame oil, water and mixtures thereof. Excipients forpreparation of compositions comprising a compound of this invention tobe administered osmotically include, for example,chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention to be administered parenterally include, for example,1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germoil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention to be administered rectally or vaginally include, for example,cocoa butter, polyethylene glycol, wax and mixtures thereof.

Compounds are expected to be useful when used with alkylating agents,angiogenesis inhibitors, antibodies, antimetabolites, antimitoties,antiproliferatives, antivirals, aurora kinase inhibitors, otherapoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors,activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viraloncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors,heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC)inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitorsof apoptosis proteins (1APs), intercalating antibiotics, kinaseinhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target ofrapamycin inhibitors, microRNA's, mitogen-activated extracellularsignal-regulated kinase inhibitors, multivalent binding proteins,non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosinediphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidinc, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-(3-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanylmethyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofuran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR™ (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds of this invention may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); 0: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),cniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epithilone B), GARDASTL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECTN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Determination of Biological Activity

Assays for the inhibition of Bcl-2 family proteins, using Bcl-xL as arepresentative example, were performed in 96-well microtiter plates.Compounds of the present invention were diluted in DMSO toconcentrations between 10 M and 10 μM and introduced into each cell ofthe plate. A mixture totaling 125 L per well of assay buffer (20 mMphosphate buffer (pH 7.4), 1 mM EDTA, 50 mM NaCl, 0.05% pluronic F-68),6 nM of BCL-X_(L) protein (prepared according to the procedure describedin Science 1997, 275, 983-986), 1 nM fluorescein-labeled BAD peptide(purchased from Synpep, CA), and the DMSO solution of the compound ofthe present invention was shaken for 2 minutes and placed in a LJLAnalyst (LJL Bio Systems, CA). A negative control (DMSO, 15 nM BADpeptide, assay buffer) and a positive control (DMSO, 15 nM BAD peptide,30 nM BCL-X_(L), assay buffer) were used to determine the range of theassay. Polarization was measured at room temperature using a continuousFluorescein lamp (excitation 485 nm, emission 530 nm). The K_(i) valuewas calculated directly from the mP value by Microsoft Excel.

Assays for the inhibition of Bcl-2 were performed in 96-well microtiterplates. Compounds of the instant invention were diluted in DMSO toconcentrations between 10 M and 10 μM and introduced into each well ofthe plate. A mixture totaling 125 L per well of assay buffer (20 mMphosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PF-68), 10 nM of Bcl-2protein (prepared according to the procedure described in PNAS 2001, 98,3012-3017), 1 nM fluorescein-labeled BAX peptide (prepared in-house),and the DMSO solution of the compound of the instant invention wasshaken for 2 minutes and placed in a LJL Analyst (LJL Bio Systems, CA.Polarization was measured at room temperature using a continuousFluorescein lamp (excitation 485 nm, emission 530 nm). K_(i) values werecalculated using Microsoft Excel.

Inhibition constants (K_(i)) for compounds according to the inventionare shown in TABLE 1 below. Where the K_(i) for a compound isrepresented as “>” (greater than) a certain numerical value, it isintended to mean that the binding affinity value is greater than thelimits of detection of the assay used. Where the K_(i) for a compound isrepresented as “<” (less than) a certain numerical value, it is intendedto mean that the binding affinity value is lower than the limit ofdetection of the assay used.

TABLE 1 FPA Bcl-2 Binding Ki (μM) Example Bcl-2 FPA Example Bcl-2 FPANo. 11 pt Ki (uM) No. 11 pt Ki (uM) 1 0.174 44 >6.245 2 0.22 45 0.079 30.065 46 0.033 4 0.19089 47 0.066928 5 0.059174 48 1.388 6 0.15496 490.342 7 1.2644 50 3.556 8 0.084635 51 1.049 9 <0.020 52 1.392 10 <0.02053 0.84492 11 1.3044 54 >9.7305 12 0.3038 55 0.35156 13 0.60807 56<0.020 14 0.047406 57 0.13387 15 <0.020 58 >18.674 16 0.039706 590.066678 17 0.030083 60 0.50423 18 <0.020 61 <0.020 19 0.6035 62 0.2807720 >51.897 63 0.27762 21 5.5988 64 1.4727 22 0.031403 65 0.9281 23<0.020 66 0.0078655 24 2.2651 67 4.0442 25 0.97859 68 0.092644 26 1.165569 0.78864 27 0.027114 70 0.03537 28 0.029579 71 <0.020 29 0.35402 720.28748 30 0.29489 73 0.093189 31 0.031861 74 0.10238 32 0.091893 750.25081 33 <0.020 76 nd 34 0.047684 77 nd 35 0.021652 78 nd 36 0.1214679 1.42 37 0.16544 80 1.303 38 0.14942 81 4.726 39 2.9135 82 2.18 400.054683 83 >6.245 41 5.186 84 2.378 42 2.479 85 2.878 43 >6.245

The inhibition constant (K_(i)) is the dissociation constant of anenzyme-inhibitor complex or a protein/small molecule complex, whereinthe small molecule is inhibiting binding of one protein to anotherprotein. So a large K_(i) value indicates a low binding affinity and asmall K_(i) value indicates a high binding affinity.

This inhibitory data demonstrates the utility of compounds havingformula (I) as inhibitors of anti-apopotic Bcl-2 protein.

It is expected that, because compounds of this invention bind to Bcl-2,they would also have utility as binders to anti-apoptotic proteinshaving close structural homology to Bcl-2, such as, for example,anti-apoptotic Bcl-X_(L), Bcl-w, Mcl-1 and Bfl-1/A1 proteins.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer spleen cancer, and the like is described in commonly-owned PCT US2004/36770, published as WO 2005/049593, and PCT US 2004/37911,published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.

Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.

Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but arc not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds of this invention would inhibitgrowth of cells expressing Bcl-2 proteins derived from a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia areata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,colorectal common varied immunodeficiency (common variablehypogammaglobulinaemia), conjunctivitis, connective tissue diseaseassociated interstitial lung disease, contact dermatitis, Coombspositive haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease,cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis,culture negative sepsis, cystic fibrosis, cytokine therapy associateddisorders, Crohn's disease, dementia pugilistica, demyelinatingdiseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma,dermatologic conditions, dermatomyositis/polymyositis associated lungdisease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus,Diffuse Lewy body disease, dilated cardiomyopathy, dilated congestivecardiomyopathy, discoid lupus erythematosus, disorders of the basalganglia, disseminated intravascular coagulation, Down's Syndrome inmiddle age, drug-induced interstitial lung disease, drug-inducedhepatitis, drug-induced movement disorders induced by drugs which blockCNS dopamine, receptors, drug sensitivity, eczema, encephalomyelitis,endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis,Epstein-Barr virus infection, erythromelalgia, extrapyramidal andcerebellar disorders, familial hematophagocytic lymphohistiocytosis,fetal thymus implant rejection, Friedreich's ataxia, functionalperipheral arterial disorders, female infertility, fibrosis, fibroticlung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cellarteritis, glomerular nephritis, glomerulonephritides, Goodpasture'ssyndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease),gouty arthritis, graft rejection of any organ or tissue, graft versushost disease, gram negative sepsis, gram positive sepsis, granulomas dueto intracellular organisms, group B streptococci (GBS) infection,Grave's disease, haemosiderosis associated lung disease, hairy cellleukemia, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto'sthyroiditis, hay fever, heart transplant rejection, hemachromatosis,hematopoietic malignancies (leukemia and lymphoma), hemolytic anemia,hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura,hemorrhage, Henoch-Schoenlcin purpurca, Hepatitis A, Hepatitis B,Hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease,hypoparathyroidism, Huntington's chorea, hyperkinetic movementdisorders, hypersensitivity reactions, hypersensitivity pneumonitis,hyperthyroidism, hypokinetic movement disorders,hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison'sdisease, idiopathic leucopaenia, idiopathic pulmonary fibrosis,idiopathic thrombocytopaenia, idiosyncratic liver disease, infantilespinal muscular atrophy, infectious diseases, inflammation of the aorta,inflammatory bowel disease, insulin dependent diabetes mellitus,interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis,ischemia-reperfusion injury, ischemic stroke, juvenile perniciousanaemia, juvenile rheumatoid arthritis, juvenile spinal muscularatrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplantrejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myelodyplasticsyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaceus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherlosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Raynoud's disease, Refsum's disease, regularnarrow QRS tachycardia, Reiter's disease, renal disease NOS,renovascular hypertension, reperfusion injury, restrictivecardiomyopathy, rheumatoid arthritis associated interstitial lungdisease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease associated lung disease, Sjörgren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthropathy,spondyloarthopathy, sporadic, polyglandular deficiency type I sporadic,polyglandular deficiency type II, Still's disease, streptococcalmyositis, stroke, structural lesions of the cerebellum, Subacutesclerosing panencephalitis, sympathetic ophthalmia, Syncope, syphilis ofthe cardiovascular system, systemic anaphylaxis, systemic inflammatoryresponse syndrome, systemic onset juvenile rheumatoid arthritis,systemic lupus erythematosus, systemic lupus erythematosus-associatedlung disease, systemic sclerosis, systemic sclerosis-associatedinterstitial lung disease, T-cell or FAB ALL, Takayasu'sdisease/arteritis, Telangiectasia, Th2 Type and Th1 Type mediateddiseases, thromboangitis obliterans, thrombocytopenia, thyroiditis,toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, type-2autoimmune hepatitis (anti-LKM antibody hepatitis), type B insulinresistance with acanthosis nigricans, type III hypersensitivityreactions, type IV hypersensitivity, ulcerative colitic arthropathy,ulcerative colitis, unstable angina, uremia, urosepsis, urticaria,uveitis, valvular heart diseases, varicose veins, vasculitis, vasculiticdiffuse lung disease, venous diseases, venous thrombosis, ventricularfibrillation, vitiligo acute liver disease, viral and fungal infections,vital encephalitis/aseptic meningitis, vital-associated hemaphagocyticsyndrome, Wegener's granulomatosis, Wernicke-Korsakoff syndrome,Wilson's disease, xenograft rejection of any organ or tissue, yersiniaand salmonella-associated arthropathy and the like.

Schemes and Experimentals

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-13 means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC.HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

Compounds of this invention may be made by synthetic chemical processes,examples of which are shown herein. Exemplary schemes of the most usefuland readily understood description of procedures and conceptual aspectsof this invention are disclosed in commonly-owned U.S. patentapplication Ser. No. 12/631,367, and 12/631,404. It is meant to beunderstood that the order of the steps in the processes may be varied,that reagents, solvents and reaction conditions may be substituted forthose specifically mentioned, and that vulnerable moieties may beprotected and deprotected, as necessary.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds andintermediates were named using ACD/ChemSketch Version 12.01 (13 May2009), Advanced Chemistry Development Inc., Toronto, Ontario), orChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

Example 14-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}phenyl)sulfonyl]benzamideExample 1A 4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 1A was prepared using methods described by Bruncko, et. al., J.Med. Chem. 2007, 50, 641-662.

Example 1BN-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzamide

EXAMPLE 1A (10 g), 4-chloro-3-nitrobenzenesulfonamide (5.82 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.42 g)and 4-dimethylaminopyridine (3.00 g) were combined in dichloromethane(98 ml). The mixture was stirred at room temperature overnight, dilutedwith dichloromethane, and poured into water. The organic layer waswashed thoroughly with water, and washed with 1M aqueous HCl solutionand 5% aqueous NaHCO₃ solution. The organic layer was washed again withwater and brine. The organic layer was dried over MgSO₄, filtered, andthe filtrate was concentrated under vacuum. The crude material waspurified by flash chromatography, eluting with a gradient of 2%methanol/dichloromethane to 10% methanol/dichloromethane. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 12.08 (br s, 1H), 8.64 (d, 1H), 8.37 (d,1H), 7.94 (dd, 1H), 7.75 (m, 3H), 7.54 (m, 4H), 7.40 (m, 2H), 7.35 (d,2H), 6.93 (d, 2H), 4.39 (br s, 1H), 4.02 (m, 1H), 3.91 (br s, 2H), 3.28(br s, 2H), 3.08 (br s, 3H), 2.89 (br s, 2H), 2.73 (m, 1H), 2.40 (m,1H), 2.09 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.64 (m, 1H), 1.24 (s,3H), 1.12 (d, 3H), 1.08 (s, 3H).

Example 1C4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}phenyl)sulfonyl]benzamide

EXAMPLE 1B (40 mg) and(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (19.60 mg)were combined in dioxane (1 ml). Triethylamine (0.027 ml) was added. Themixture was heated to 90° C. overnight, concentrated under vacuum, andpurified by preparative HPLC using a C18 column, 250×21.20 mm, 5μ, andeluting with a gradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acidin water, giving the product as a trifluoroacetate salt. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 12.08 (br s, 1H), 8.64 (d, 1H), 8.37 (d,1H), 7.94 (dd, 1H), 7.75 (m, 3H), 7.54 (m, 4H), 7.40 (m, 2H), 7.35 (d,2H), 6.93 (d, 2H), 4.39 (br s, 1H), 4.02 (m, 1H), 3.91 (br s, 2H), 3.28(br s, 2H), 3.08 (br s, 3H), 2.89 (br s, 2H), 2.73 (m, 1H), 2.40 (m,1H), 2.09 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.64 (m, 1H), 1.24 (s,3H), 1.12 (d, 3H), 1.08 (s, 3H).

Example 24-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 2A4-{4-[acetyl-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid ethyl ester

EXAMPLE 45C (50 mg) was dissolved in dichloromethane (2 mL).Triethylamine (0.022 mL, 16 mg) was added, followed by acetyl chloride(0.010 mL, 11 mg). The solution was mixed at room temperature for 16hours and then purified by flash column chromatography on silica gelusing 30% ethyl acetate in hexanes to afford the title compound.

Example 2B4-{4-[Acetyl-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid

EXAMPLE 2A (55 mg) was dissolved in tetrahydrofuran (0.6 mL), methanol(0.2 mL), and water (0.2 mL) and treated with lithium hydroxidemonohydrate (22 mg). The solution was stirred at room temperature for 16hours. The solution was acidified with 1M hydrochloric acid, extractedwith ethyl acetate, dried with anhydrous sodium sulfate, filtered, andconcentrated to afford the title compound.

Example 2C 4-Fluoro-3-nitro-benzenesulfonamide

2-Fluoronitrobenzene (141 g, 1.0 mol) and chlorosulfonic acid (300 mL)were heated at 60° C. for 10 hours. After the reaction mixture cooled toroom temperature, it was carefully poured to ice (about 1 kg) in a fourliter Erlenmeyer flask and cooled efficiently by an ice-brine bath. Themixture was extracted with ether (4 L), and brine (2 L). The resultingsolution was cooled to −40° C. Concentrated ammonium hydroxide (300 mL)was then added with vigorous stirring, and the addition rate wascontrolled to allow the reaction mixture to stay below −10° C. (internaltemperature). Dry ice cubes were added to the reaction mixture to lowerthe temperature when necessary. Immediately after the addition wascomplete, the resulting mixture was separated, and the aqueous phase wasextracted with ethyl acetate (2 L). The combined organic phases werewashed with the aqueous 4 M hydrochloric acid (300 mL) and brine (100mL), dried on anhydrous magnesium sulfate, filtered, and concentrated.The resulting solid was recrystallized from ethyl acetate/hexanemixture. The mother liquid from the recrystallization was concentratedand recrystallized in the same manner, and the resulting solids werecombined to afford the title compound.

Example 2D 4-(Cyclohexylmethyl-amino)-3-nitro-benzenesulfonamide

To a solution of EXAMPLE 2C (7.70 g) in tetrahydrofuran (35 mL) wasadded dropwise a solution of cyclohexylmethylamine (6.0 mL, 5.22 g) anddiisopropylethylamine (8.0 mL, 5.92 g) in tetrahydrofuran (15 mL). Afterthe addition, tetrahydrofuran (20 mL) was added, and the reaction wasstirred at room temperature for 16 hours. The solution was added towater and extracted with a solution of ethyl acetate and dichloromethane(1:1 by volume). The solution was dried over anhydrous sodium sulfate,filtered, and the filtrate volume was reduced to isolate the titlecompound by crystallization.

Example 2E4-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 2B for EXAMPLE1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.50 (br s, 1H), 8.40 (m, 1H),7.88 (dd, 1H), 7.73 (d, 1H), 7.71 (d, 1H), 7.06 (dd, 1H), 6.86 (d, 1H),6.81 (d, 1H), 4.16 (m, 1H), 3.96-3.77 (m, 2H), 3.25 (t, 4H), 3.18-3.06(m, 2H), 2.77 (m, 4H), 2.48-2.23 (m, 2H), 2.14-1.95 (m, 8H), 1.86 (m,2H), 1.77-1.60 (m, 11H), 1.25-1.14 (m, 8H), 1.07-1.00 (m, 4H), 0.95-0.86(m, 2H).

Example 34-(4-{benzoyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 3A4-{4-[Benzoyl-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid ethyl ester

The title compound was prepared by substituting benzoyl chloride foracetyl chloride in EXAMPLE 2A.

Example 3B4-{4-[Benzoyl-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 3A for EXAMPLE2A in EXAMPLE 2B.

Example 3C4-(4-{benzoyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 3B for EXAMPLE1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.98 (br s, 1H), 8.51 (br s,1H), 8.42 (br s, 1H), 7.89 (dd, 1H), 7.43 (d, 2H), 7.42 (m, 3H), 7.29(d, 2H), 7.08 (d, 1H), 6.85 (d, 2H), 4.03-3.75 (m, 3H), 3.24 (t, 4H),2.86 (m, 2H), 2.37 (m, 2H), 2.11 (m, 2H), 1.97-1.82 (m, 2H), 1.78-1.55(m, 10H), 1.23-0.91 (m, 11H), 0.79 (d, 2H), 0.45 (s, 1H).

Example 4N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamideExample 4A methyl 3′-bromobiphenyl-4-carboxylate

4-(Methoxycarbonyl)phenylboronic acid (1.55 g, 8.63 mmol),1-bromo-3-iodobenzene (2.22 g, 7.84 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.29 g,0.392 mmol), and CsF (2.38 g, 15.7 mmol) in dioxane (40 mL) were stirredat 80° C. for 8 hours. The reaction was cooled, poured into ethylacetate, washed twice with water and brine, and the combined organiclayers were concentrated. The residue was chromatographed on silica gelusing 2-20% ethyl acetate in hexanes afford the title compound.

Example 4B methyl3′-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)biphenyl-4-carboxylate

EXAMPLE 4A (146 mg, 0.50 mmol),(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (92 mg, 0.60mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol),tri-t-butylphosphonium tetrafluoroborate (11.7 mg, 0.04 mmol), and K₃PO₄(160 mg, 0.75 mmol) in diglyme (5 mL) were stirred at 100° C. for 24hours. The reaction was cooled and was chromatographed on silica gelusing 5% ethyl acetate in hexanes to afford the title compound.

Example 4C3′-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)biphenyl-4-carboxylicacid

The title compound was prepared as described in EXAMPLE 2B using EXAMPLE4B in place of EXAMPLE 2A.

Example 4DN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE4C in place of EXAMPLE 1A and EXAMPLE 2D in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (s, 1H), 8.65 (m, 2H), 7.97 (d, 1H), 7.93(d, 2H), 7.68 (d, 2H), 7.28 (d, 1H), 7.17 (t, 1H), 6.88 (s, 1H), 6.82(d, 1H), 6.66 (d, 1H), 5.70 (m, 1H), 3.65 (m, 1H), 2.55 (m, 2H), 2.34(m, 4H), 1.72 (m, 6H), 1.52 (m, 1H), 0.99-1.49 (m, 16H).

Example 5N-({4-[cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(phenylacetyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamideExample 5A4-{4-[Phenylacetyl-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid ethyl ester

The title compound was prepared by substituting phenyl acetyl chloridefor acetyl chloride in EXAMPLE 2A.

Example 5B4-{4-[Phenylacetyl-01S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 5A for EXAMPLE2A in EXAMPLE 2B.

Example 5CN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(phenylacetyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 5B for EXAMPLE1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.98 (br s, 1H), 8.63 (m, 2H),7.93 (dt, 1H), 7.73 (d, 1H), 7.71 (d, 1H), 7.33-7.19 (m, 6H), 6.91 (d,2H), 4.10 (m, 1H), 3.95 (m, 2H), 3.78 (d, 1H), 3.29 (t, 4H), 3.00-2.60(m, 4H), 2.34 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1H), 1.90 (m, 1H),1.80-1.53 (m, 9H), 1.23-1.17 (m, 8H), 0.99 (m, 2H), 0.92-0.86 (m, 6H).

Example 6N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide Example 6A methyl4′-bromobiphenyl-4-carboxylate

The title compound was prepared as described in EXAMPLE 4A using1-bromo-4-iodobenzene in place of 1-bromo-3-iodobenzene.

Example 6B methyl4′-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)biphenyl-4-carboxylate

The title compound was prepared as described in EXAMPLE 4B using EXAMPLE6A in place of EXAMPLE 4A.

Example 6C4′-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)biphenyl-4-carboxylicacid

The title compound was prepared as described in EXAMPLE 2B using EXAMPLE6B in place of EXAMPLE 2A.

Example 6DN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE6C in place of EXAMPLE 1A and EXAMPLE 2D in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (s, 1H), 8.66 (m, 2H), 7.97 (d, 1H), 7.87(d, 2H), 7.66 (d, 2H), 7.51 (d, 2H), 7.26 (d, 2H), 7.18 (m, 1H), 6.79(d, 2H), 5.95 (m, 1H), 3.65 (m, 1H), 2.60 (m, 2H), 2.33 (m, 2H), 1.94(m, 2H), 1.72 (m, 6H), 1.23 (s, 3H), 1.19 (m, 4H), 0.93-1.15 (m, 11H).

Example 7N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamideExample 7A4′-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)amino)biphenyl-4-carboxylicacid

EXAMPLE 6C (100 mg, 0.286 mmol), 3-phenylpropanal (101 mg, 0.715 mmol),and sodium triacetoxyborohydride (182 mg, 0.858 mmol) was stirred in1,2-dichloroethane (5 mL) for 24 hours. The mixture was triturated withdichloromethane and ether to afford the title compound.

Example 7BN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE7A in place of EXAMPLE 1A and EXAMPLE 2D in place of4-chloro-3-nitrobenzenesulfonamide.

Example 84-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 8A benzyl2-(4-(ethoxycarbonyl)phenyl)-2,6-diazabicyclo[3.2.1]octane-6-carboxylate

Benzyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate (300 mg) wasdissolved in dimethylsulfoxide (3 mL), then ethyl 4-fluorobenzoate (172mg) and potassium carbonate (206 mg) were added. The reaction was heatedat 130° C. overnight. After cooling, the reaction was diluted with waterand extracted with ethyl acetate. The organic layer was washed withbrine and dried over sodium sulfate. After filtration and concentrationof the filtrate, the resultant crude material was purified by columnchromatography on silica gel using 7/3 hexanes/ethyl acetate to affordthe title compound.

Example 8B ethyl 4-(2,6-diazabicyclo[3.2.1]octan-2-yl)benzoate

EXAMPLE 8A (82 mg) was dissolved in methanol (6 mL), then 10% palladiumon carbon (13 mg) was added, and the reaction stirred under a hydrogenballoon for 3 hours. The reaction was then filtered through celite andthe filtrate was concentrated, giving the crude product that was used inthe next step with no purification.

Example 8C ethyl4-{6-[adamantan-1-ylcarbonyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}benzoate

EXAMPLE 8B (45 mg) and adamantane-1-carboxylic acid (31 mg) weredissolved in dichloromethane (1 mL), then1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (38 mg),and 4-dimethylaminopyridine (7 mg) were added and the reaction stirredat room temperature overnight. The reaction was then diluted with ethylacetate and washed with twice with 1M H₃PO₄, twice with saturatedNaHCO₃, and once with brine. The organic layer was dried over sodiumsulfate. After filtration and concentration, the title compound wascarried on with no further purification.

Example 8D ethyl4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}benzoate

EXAMPLE 8C (70 mg) was dissolved in tetrandyrofuran (2 mL), then a 1.0Msolution of borane in tetrahydrofuran (0.25 mL) was added and thereaction heated at 70° C. for one hour. After cooling to roomtemperature, 2.5M HCl in ethanol (2 mL) was added and the reactionheated at 70° C. for one hour. After cooling and concentration theresidue was redissolved in 2.5M HCl in ethanol (4 mL) and heated at 70°C. for one hour. The reaction was then cooled to room temperature andpartitioned between ethyl acetate and 2M aqueous Na₂CO₃. The organiclayer was washed with brine and dried over sodium sulfate. Afterfiltration and concentration the resultant product was carried onwithout further purification.

Example 8E4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}benzoic acid

EXAMPLE 8D (68 mg) was dissolved in tetrahydrofuran (1 mL) and methanol(1 mL). Then 1N aqueous lithium hydroxide was added (0.32 mL) and themixture was heated at 65° C. overnight. The reaction was then cooled andconcentrated, and water was added, adjusting the pH to 1 with 2N aqueousHCl. The reaction mixture was extracted with chloroform/methanol, andafter drying the organic layer over sodium sulfate and filtration, thefiltrate was concentrated to afford the title compound as ahydrochloride salt.

Example 8F4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

EXAMPLE 8E (32 mg), EXAMPLE 2D (30 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (32 mg),and 4-dimethylaminopyridine (20 mg) were stirred in dichloromethane (1.5mL) for 24 hours. The product was purified by preparative HPLC using aC18 column, 250×50 mm, 10u, and eluting with a gradient of 20-100% CH₃CNvs. 0.1% trifluoroacetic acid in water, giving the product as atrifluoroacetate salt. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.05(br s, 1H), 8.79 (br s, 1H), 8.63 (m, 2H), 7.93 (dd, 1H), 7.78 (d, 2H),7.26 (d, 1H), 6.90 (m, 2H), 4.90 (br m, 1H), 4.15 (br m, 1H), 3.90 (brm, 1H), 3.76 (br m, 1H), 3.26 (m, 4H), 3.12 (s, 2H), 2.08 (br m, 2H),1.99 (br m, 5H), 1.60 (m, 18H), 1.18 (m, 3H), 1.00 (m, 2H).

Example 9N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamideExample 9A4-((R)-3-Morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide

The title compound was prepared as described by Park, Cheol-Min; at. alJ. Med. Chem 2008, 51, 6902-6915.

Example 9B4-{-4-[3-Phenyl-propionyl)-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid ethyl ester

The title compound was prepared by substituting 3-phenylpropionylchloride for acetyl chloride in EXAMPLE 2A.

Example 9C4-{4-[(3-Phenyl-propionyl)-((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amino]-piperidin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 9B for EXAMPLE2A in EXAMPLE 2B.

Example 9DN-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 9C for EXAMPLE1A and EXAMPLE 9A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.10 (dd, 1H), 7.94 (dt, 1H),7.72 (d, 2H), 7.39-7.13 (m, 10H), 6.97-6.78 (m, 4H), 4.20 (m, 1H), 4.04(m, 1H), 3.88 (m, 2H), 3.51 (br s, 4H), 2.92-2.63 (m, 7H), 2.45-2.03 (m,8H), 1.95 (m, 2H), 1.85-1.54 (m, 4H), 1.41 (m, 2H), 1.24-1.15 (m, 8H),1.01-0.90 (m, 6H).

Example 104-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 10A ethyl 4-(piperazin-1-yl)benzoate

The title compound was prepared by the methods described in Bruncko, M.,et. al., J. Med. Chem., 2007 50, 641.

Example 10B ethyl 4-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}benzoate

The title compound was prepared by substituting EXAMPLE 10A for EXAMPLE8B in EXAMPLE 8C.

Example 10C ethyl 4-{-4-[adamantan-1-ylmethyl]piperazin-1-yl}benzoate

The title compound was prepared by substituting EXAMPLE 10B for EXAMPLE8C in EXAMPLE 8D.

Example 10D 4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}benzoic acid

The title compound was prepared by substituting EXAMPLE 10C for EXAMPLE8D in EXAMPLE 8E.

Example 10E(R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by the methods described in Wendt, M.,et. al., J. Med. Chem., 2006, 49, 1165.

Example 10F4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 10D for EXAMPLE8E and EXAMPLE 10E for EXAMPLE 2D in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 9.82 (v br s, 1H), 9.02 (v br s, 1H), 8.57 (d,1H), 8.30 (d, 2H), 7.87 (dd, 1H), 7.80 (d, 2H), 7.23 (m, 2H), 7.16 (m,4H), 7.01 (d, 2H), 4.20 (m, 2H), 3.90 (br m, 2H), 3.60, 3.40, 3.20, 3.00(all br m, total 18H), 2.18 (m, 2H) 1.99 (br s, 3H), 1.62 (br m, 10H).

Example 11 4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 11A tert-butyl(1S,4S)-5-[4-(ethoxycarbonyl)phenyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

The title compound was prepared by substituting tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate for benzyl2,6-diazabicyclo[3.2.1]octane-6-carboxylate in EXAMPLE 8A.

Example 11B ethyl 4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzoate

EXAMPLE 11A (280 mg) was dissolved in 4N HCl in dioxane (6 mL) andstirred at room temperature for one hour. The reaction was thenpartitioned between ethyl acetate and saturated NaHCO₃. The organiclayer was washed with brine and dried over sodium sulfate. Afterfiltration and concentration the resultant product was carried on withno purification.

Example 11C ethyl4-{(1S,4S)-5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}benzoate

The title compound was prepared by substituting EXAMPLE 11B for EXAMPLE8B in EXAMPLE 8C.

Example 11D ethyl4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}benzoate

The title compound was prepared by substituting EXAMPLE 11C for EXAMPLE8C in EXAMPLE 8D.

Example 11E4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}benzoicacid

The title compound was prepared by substituting EXAMPLE 11D for EXAMPLE8D in EXAMPLE 8E.

Example 11F 4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 11E for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.05 (br s,1H), 8.63 (m, 2H), 8.20 (br s, 1H), 7.93 (dd, 1H), 7.78 (d, 2H), 7.26(d, 1H), 6.70 (m, 2H), 4.78 (br s, 1H), 4.44 (br s, 1H), 3.70 (m, 2H),3.38 (m, 2H), 3.30 (t, 2H), 3.12 (s, 2H), 2.38 (m, 1H), 2.20 (m, 1H),1.99 (br m, 3H), 1.60 (m, 18H), 1.18 (m, 3H), 1.00 (m, 2H).

Example 124-(4-{[3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 12A ethyl4-(4-{[3-bromo-5-methyladamantan-1-yl]carbonyl}piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 10A for EXAMPLE8B and 3-methyl-5-bromo-adamantane-1-carboxylic acid foradamantane-1-carboxylic acid in EXAMPLE 8C.

Example 12B ethyl4-(4-{[3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 12A for EXAMPLE8C in EXAMPLE 8D.

Example 12C4-(4-{[3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)benzoic acid

The title compound was prepared by substituting EXAMPLE 12B for EXAMPLE8D in EXAMPLE 8E.

Example 12D 4-(4-{[3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 12C for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.05 (v brs, 1H), 8.97 (v br s, 1H), 8.63 (m, 2H), 7.93 (dd, 1H), 7.80 (d, 2H),7.25 (d, 1H), 7.00 (d, 2H), 3.90 (br m, 1H), 3.60, 3.40, 3.20, 3.00 (allbr m, total 10H), 2.21 (s, 5H) 2.02 (m, 2H), 1.70 (m, 7H), 1.40 (m, 5H),1.20 (m, 4H), 1.00 (m, 2H), 0.86 (s, 3H).

Example 13N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzamideExample 13A ethyl4-(4-{[3,5-dimethyladamantan-1-yl]carbonyl}piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 10A for EXAMPLE8B and 3,5-dimethyl-adamantane-1-carboxylic acid foradamantane-1-carboxylic acid in EXAMPLE 8C.

Example 13B ethyl4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 13A for EXAMPLE8C in EXAMPLE 8D.

Example 13C4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzoic acid

The title compound was prepared by substituting EXAMPLE 13B for EXAMPLE8D in EXAMPLE 8E.

Example 13DN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 13C for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.05 (v brs, 1H), 8.97 (v br s, 1H), 8.63 (m, 2H), 7.93 (dd, 1H), 7.80 (d, 2H),7.25 (d, 1H), 7.00 (d, 2H), 3.90 (br m, 1H), 3.55 (br m, 1H), 3.30 (m,8H), 2.99 (br s, 2H), 2.08 (br m, 1H), 1.70 (m, 7H), 1.45 (s, 2H), 1.20(m, 12H), 1.00 (m, 2H), 0.82 (s, 6H).

Example 144-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(1-methyl-2-oxo-3-azabicyclo[3.1.1]hept-3-yl)phenyl]sulfonyl}benzamide

EXAMPLE 14 was prepared according to the procedure for EXAMPLE 1Bsubstituting4-(1-methyl-2-oxo-3-azabicyclo[3.1.1]heptan-3-yl)benzenesulfonamide for4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.45 (s, 3H), 1.56 (dd, 1H), 1.92-1.98 (m,1H), 2.63 (dd, 1H), 2.69-2.75 (m, 1H), 2.79-2.99 (m, 2H), 3.01-3.21 (m,4H), 3.30-3.35 (m, 4H), 3.78-4.01 (m, 1H), 4.39 (s, 2H), 6.88-6.95 (m,2H), 7.29-7.36 (m, 1H), 7.38-7.44 (m, 2H), 7.47-7.58 (m, 6H), 7.72-7.79(m, 3H), 7.99-8.06 (m, 2H), 9.45-9.59 (m, 1H).

Example 15N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamideExample 15A ethyl4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzoate

EXAMPLE 62A (100 mg),(1S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-ylboronic acid (44.6mg), tris(dibenzylideneacetone)dipalladium(0) (11 mg),tri-t-butylphosphonium tetrafluoroborate (4 mg) and CsF (113 mg) weredissolved in anhydrous tetrahydrofuran (2 mL). The reaction mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated, and the crude material was purified using flashchromotography with 0-15% ethyl acetate/hexane to afford the titlecompound.

Example 15B4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 15A for EXAMPLE2A in EXAMPLE 2B.

Example 15CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 15B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.12 (m, 1H), 8.66 (m, 2H),7.94 (dd, 1H), 7.79 (d, 2H), 7.64 (m, 1H), 7.41 (m, 2H), 7.30 (d, 1H),7.20 (m, 1H), 6.99 (d, 2H), 6.01 (d, 1H), 4.28 (m, 2H), 3.85 (m, 2H),3.28 (m, 12H), 1.92 (m, 2H), 1.62 (m, 3H), 1.24 (m, 5H), 0.94 (s, 3H),0.83 (d, 6H).

Example 16N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzamideExample 16A ethyl 4-(4-(2-nitrobenzyl)piperazin-1-yl)benzoate

Ethyl 4-(piperazin-1-yl)benzoate (1.5 g), 1-(bromomethyl)-2-nitrobenzene(1.383 g) and sodium carbonate (2.036 g) were suspended in anhydrousN,N-dimethylformamide (20 mL) at room temperature for 4 hours. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine, and concentrated. The residue was purified by flash columnpurification with 10-40% ethyl acetate/hexane to afford the titlecompound.

Example 16B Ethyl 4-(4-(2-aminobenzyl)piperazin-1-yl)benzoate

EXAMPLE 16A (1.5 g) and 5% Pd/C (0.3 g) were suspended in anhydrousethanol (75 mL). The reaction mixture was stirred under 1 atmospherehydrogen for 2 hours. The mixture was filtered, and the filtrate wasconcentrated to afford the product.

Example 16C ethyl4-(4-{2-[octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzoate

The title compound was prepared by substitutingtricyclo[5.2.1.02,6]decan-8-one for 2-formylphenylboronic acid andEXAMPLE 16B for EXAMPLE 23C in EXAMPLE 40A.

Example 16D4-(4-{2-[octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 16C for EXAMPLE2A in EXAMPLE 2B.

Example 16EN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 16D for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.09 (bs, 1H), 8.66 (m, 2H),7.94 (dd, 1H), 7.79 (d, 2H), 7.30 (d, 1H), 7.22 (t, 2H), 7.01 (m, 2H),6.72 (d, 1H), 6.65 (m, 1H), 4.26 (m, 2H), 3.85 (dd, 2H), 3.66 (m, 2H),3.28 (m, 10H), 2.26-1.61 (m, 14H), 1.40-0.92 (m, 8H).

Example 17N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]hept-2-yl]amino}benzyl)piperazin-1-yl]benzamideExample 17A ethyl4-(4-(2-((1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]heptan-2-ylamino)benzyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one for2-formylphenylboronic acid and EXAMPLE 16B for EXAMPLE 23C in EXAMPLE40A.

Example 17B

Ethyl4-(4-(2-((1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]heptan-2-ylamino)benzyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 17A for EXAMPLE2A in EXAMPLE 2B.

Example 17CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]hept-2-yl]amino}benzyl)piperazin-1-yl]benzamide

The title compound was prepared by substituting EXAMPLE 17B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.06 (bs, 1H), 8.64 (m, 2H),7.94 (m, 1H), 7.79 (d, 2H), 7.30 (d, 1H), 7.20 (m, 2H), 7.00 (d, 2H),6.65 (m, 2H), 3.83 (m, 2H), 3.61 (m, 2H), 3.30 (m, 14H), 2.05 (s, 1H),1.86 (m, 3H), 1.61 (m, 4H), 1.45 (m, 1H), 1.28 (m, 3H), 0.99 (s, 3H),0.86 (s, 3H), 0.77 (d, 3H).

Example 18 4-[4-(2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]aminobenzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 18A Ethyl4-(4-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-ylamino)benzyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting(1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one for 2-formylphenylboronicacid and EXAMPLE 16B for EXAMPLE 23C in EXAMPLE 40A.

Example 18B4-(4-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-ylamino)benzyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 18A for EXAMPLE2A in EXAMPLE 2B.

Example 18C4-[4-(2-{[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 18B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.09 (s, 1H), 8.66 (m, 2H),7.94 (dd, 1H), 7.79 (d, 2H), 7.30 (d, 1H), 7.19 (m, 2H), 6.99 (d, 2H),6.59 (m, 2H), 3.85 (m, 4H), 3.29 (m, 14H), 2.33 (m, 2H), 2.17 (m, 1H),1.82 (m, 7H), 1.27 (dd, 2H), 1.18 (s, 3H), 1.09 (s, 3H), 1.03 (d, 1H).

Example 194-(4-{[(1R,5R)-2-(4-chlorophenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 19A (1R,5R)-6,6-Dimethyl-3-methylene-bicyclo[3.1.1]heptan-2-one

(1R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-2-one (0.938 mL, 920 mg) wasadded to tetrahydrofuran (50 mL) and the mixture was cooled to −78° C.using an isopropanol/dry ice bath. Lithium bis(trimethylsilyl)amide (1Min tetrahydrofuran, 7.99 mL) was added, and the solution was stirred at−78° C. for 15 minutes. The solution was allowed to warm to 0° C. in awater/ice bath and the mixture was stirred for 45 minutes.Paraformaldehyde (2000 mg) was added. The solution was stirred at 0° C.for 15 minutes, allowed to warm to room temperature and stir for anadditional four hours. The reaction was quenched with saturated aqueousammonium chloride, extracted with diethyl ether, washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by flash column chromatography on silica gel using 5% ethylacetate in hexanes.

Example 19B4-[4-((1R,5R)-6,6-Dimethyl-2-oxo-bicyclo[3.1.1]hept-3-ylmethyl)-piperazin-1-yl]-benzoicacid ethyl ester

EXAMPLE 19A (417 mg) and ethyl 4-(piperazin-1-yl)benzoate (520 mg) wereadded to acetonitrile (6 mL). Bismuth (III) trifluoromethanesulfonate(113 mg) was added, and the mixture was heated at 50° C. for 5.5 hours.The mixture was cooled and purified by flash column chromatography onsilica gel using 5% methanol in dichloromethane.

Example 19C4-{4-[(1R,5R)-2-(4-Chloro-phenyl)-2-hydroxy-6,6-dimethyl-bicyclo[3.1.1]hept-3-ylmethyl]-piperazin-1-yl}-benzoicacid ethyl ester

EXAMPLE 19B (452 mg) was dissolved in tetrahydrofuran (10 mL) and themixture was cooled to −60° C. using a chloroform/dry ice bath.(4-Chlorophenyl)magnesium bromide (1M in tetrahydrofuran, 2.35 mL) wasadded drop-wise. Upon completion of the addition, the mixture was warmedquickly to −25° C. using a carbon tetrachloride/dry ice bath and stirredfor four hours. The reaction was quenched with saturated aqueousammonium chloride, extracted with ethyl acetate, dried on anhydroussodium sulfate, and purified by flash column chromatography on silicagel using 20% ethyl acetate in hexanes.

Example 19D4-{4-[(1R,5R)-2-(4-Chloro-phenyl)-6,6-dimethyl-bicyclo[3.1.1]hept-2-en-3-ylmethyl]-piperazin-1-yl}-benzoicacid ethyl ester

EXAMPLE 19C (363 mg) was dissolved in tetrahydrofuran (6 mL) and Burgessreagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide, innersalt, 209 mg) was added. The solution was stirred at room temperaturefor 16 hours and purified by flash column chromatography on silica gelusing 20% ethyl acetate in hexanes.

Example 19E4-{4-[(1R,5R)-2-(4-Chloro-phenyl)-6,6-dimethyl-bicyclo[3.1.1]hept-2-en-3-ylmethyl]-piperazin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 19D for EXAMPLE2A in EXAMPLE 2B.

Example 19F4-(4-{[(1R,5R)-2-(4-chlorophenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 19E for EXAMPLE1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d_(o)) δ 8.56 (m, 1H), 8.48 (m, 1H),7.90 (dd, 1H), 7.76 (d, 2H), 7.48 (d, 1H), 7.40 (d, 1H), 7.14 (d, 1H),6.91 (d, 2H), 6.88 (d, 1H), 6.42 (d, 1H), 4.14 (dd, 1H), 3.26 (m, 8H),2.71 (br s, 2H), 1.95 (m, 2H), 1.77-1.53 (m, 8H), 1.33-1.11 (m, 6H),1.07 (s, 3H), 0.97 (s, 3H), 0.86 (m, 2H).

Example 204-{4-[(2-{[adamantan-2-ylmethyl]amino}-5,5-dimethylcyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 20A ethyl4-[4-({2-[(adamantan-2-ylmethyl)amino]-5,5-dimethylcyclohexyl}methyl)piperazin-1-yl]benzoate

(2-Adamantylmethyl)amine hydrochloride salt (195 mg), ethyl4-(4-((5,5-dimethyl-2-oxocyclohexypmethyl)piperazin-1-yl)benzoate (200mg) and sodium acetate (44 mg) were suspended in anhydrousdichloroethane. The reaction mixture was stirred at room temperature for20 minutes, followed by the addition of sodium triacetoxyborohydride(228 mg). The reaction mixture was stirred at room temperatureovernight. The reaction was quenched with saturated NaHCO₃ aqueoussolution. The reaction mixture was extracted with ethyl acetate, andwashed with water and brine. The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flash columnpurification with 0-5% methanol/dichloromethane to afford the titlecompound.

Example 20B4-[4-({2-[(adamantan-2-ylmethyl)amino]-5,5-dimethylcyclohexyl}methyl)piperazin-1-yl]benzoicacid

The title compound was prepared by substituting EXAMPLE 20A for EXAMPLE2A in EXAMPLE 2B.

Example 20C4-{4-[(2-{[adamantan-2-ylmethyl]amino}-5,5-dimethylcyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 20B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.05 (s, 1H), 8.65 (m, 2H),7.94 (dd, 1H), 7.78 (d, 2H), 7.30 (d, 1H), 6.99 (d, 2H), 3.83 (m, 2H),3.26 (m, 8H), 2.98 (m, 4H), 2.72 (m, 4H), 2.27 (m, 2H), 1.64 (m, 22H),1.25 (m, 5H), 0.93 (d, 6H).

Example 214-{4-[(5,5-dimethyl-2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}cyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 21A

Ethyl4-(4-((5,5-dimethyl-2-((1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)cyclohexyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine for(2-adamantylmethyl)amine hydrochloride salt in EXAMPLE 20B.

Example 21B4-(4-((5,5-dimethyl-2-((1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)cyclohexyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 21A for EXAMPLE2A in EXAMPLE 2B.

Example 21C4-{4-[(5,5-dimethyl-2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}cyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 21B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.07 (m, 1H), 8.65 (m, 2H),7.94 (dd, 1H), 7.77 (m, 2H), 7.30 (d, 1H), 6.98 (d, 2H), 3.84 (dd, 2H),3.29 (m, 10H), 2.79 (m, 6H), 2.30 (m, 4H), 1.78 (m, 11H), 1.28 (m, 3H),1.16 (m, 8H), 0.95 (m, 9H).

Example 224-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)-5-nitrobenzyl]piperazin-1-yl}N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 22A tert-butyl4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

The title compound was prepared as described in EXAMPLE 45A usingtert-butyl piperazine-1-carboxylate in place of1,4-dioxa-8-azaspiro[4.5]decane.

Example 22B 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid

The title compound was prepared as described in EXAMPLE 2B using EXAMPLE22A in place of EXAMPLE 2A.

Example 22C tert-butyl4-(4-(4-(cyclohexylmethylamino)-3-nitrophenylsulfonylcarbamoyl)phenyl)piperazine-1-carboxylate

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE22B in place of EXAMPLE 1A and EXAMPLE 2D in place of4-chloro-3-nitrobenzenesulfonamide.

Example 22DN-(4-(cyclohexylmethylamino)-3-nitrophenylsulfonyl)-4-(piperazin-1-yl)benzamidetrifluoroacetic acid salt

A solution of EXAMPLE 22C (0.85 g, 1.4 mmol) in dichloromethane (10 mL),trifluoroacetic acid (10 mL) and triethylsilane (1 mL) was stirred for24 hours. The mixture was concentrated to afford the title compound.

Example 22E4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)-5-nitrobenzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

EXAMPLE 22D (50 mg, 0.081 mmol),2-((1s,5s)-3-azabicyclo[3.2.2]nonan-3-yl)-5-nitrobenzaldehyde (27 mg,0.097 mmol), and polymer-supported sodium cyanoborohydride (41 mg, 0.097mmol) was stirred in tetrahydrofuran (1 mL) and acetic acid (0.33 mL)for 24 hours. The crude mixture was chromatographed on silica gel using10% methanol in ethyl acetate, without and then with 1% triethylamine,to afford the title compound. MS (ELSD) m/e 762 (M+H)⁺.

Example 234-(4-{2-[2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 23A3-Nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonamide

The title compound was prepared by substituting4-aminomethyltetrahydropyran for cyclohexylmethylamine in EXAMPLE 2D.

Example 23B4-(4-{3-Nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylaminocarbonyl}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared by substituting4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester forEXAMPLE 1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide inEXAMPLE 1B.

Example 23CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(piperazin-1-yl)benzamide

EXAMPLE 23B (3.813 g) was added to dichloromethane (50 mL).Triethylsilane (5.5 mL, 4.004 g) was added, followed by trifluoroaceticacid (6 mL, 8.880 g). The solution was stirred at room temperature forfive hours. Heptane was added and the solvents were removed underreduced pressure, after which, toluene was added and the solvents againremoved under reduced pressure to isolate the title compound as the monotrifluoroacetic acid salt.

Example 23D 2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yltrifluoromethanesulfonate Tricyclo[5.2.1.02,6]decan-8-one (300 mg) wasadded to tetrahydrofuran (10 mL).

Sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 2.40 mL) wasadded, and the solution was stirred at room temperature for 10 minutes.The solution was cooled to −78° C. using an isopropanol/dry ice bath,and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(857 mg) was added. The solution was allowed to warm to room temperatureand stirred for 16 hours. The reaction mixture was concentrated, dilutedwith hexanes (20 mL), filtered and again concentrated. The residue waspurified by flash column chromatography on silica gel using a gradientof 0 to 10% ethyl acetate in hexanes.

Example 23E2-(2,3,3a,4,7,7a-Hexahydro-1H-4,7-methano-inden-5-yl)-benzaldehyde

EXAMPLE 23D (941 mg), 2-formylphenylboronic acid (600 mg), potassiumphosphate, tribasic (1416 mg), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (244 mg)were added to tetrahydrofuran (15 mL) which had been degassed andflushed with nitrogen three times. The solution was heated to 60° C. andstirred for 16 hours. The solution was concentrated and purified byflash column chromatography on silica gel using 10% ethyl acetate inhexanes.

Example 23F4-(4-{2-[2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

EXAMPLE 23C (60 mg) and EXAMPLE 23E (26 mg) were added totetrahydrofuran (1 mL) and acetic acid (0.33 mL). Sodiumcyanoborohydride (2.38 mmol/g on resin, 45 mg) was added and thesolution was stirred at room temperature for 16 hours. The solution waspurified by flash column chromatography on silica gel using 5% methanolin dichloromethane to isolate the title compound as the mono acetic acidsalt. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.94 (br s, 1H), 8.63(t, 1H), 8.62 (d, 1H), 7.93 (dd, 1H), 7.73 (d, 2H), 7.42 (d, 1H),7.28-7.20 (m, 4H), 6.92 (d, 2H), 6.25 (d, 1H), 3.85 (dd, 4H), 3.60-3.41(m, 6H), 3.37-3.26 (m, 8H), 3.22 (br s, 2H), 2.75 (br s, 2H), 2.64 (brs, 2H), 2.13 (m, 4H), 1.95-1.76 (m, 6H), 1.91 (s, 3H), 1.64-1.50 (m,6H), 1.32-1.19 (m, 3H), 1.03 (m, 2H).

Example 241-[adamantan-1-yl]-4-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamideExample 24A1-[adamantan-1-yl]-4-(2-formylphenyl)-N,N-diphenyl-1H-pyrazole-3-carboxamide

1-Adamantan-1-yl-4-bromo-1H-pyrazole-3-carboxylic acid diphenylamide (47mg), 2-formylphenylboronic acid (18 mg), sodium carbonate (32 mg), andtetrakis(triphenylphosphine)palladium(0) (7 mg) were combined indimethoxyethane/ethanol/water 12/3/4 (1 mL) and heated in a CEM Discovermicrowave reactor at 180° C. for 5 minutes. The reaction was cooled,diluted with water and extracted with ethyl acetate. The organic layerwas washed with brine and dried over sodium sulfate. After filtrationand concentration, the crude material was purified by columnchromatography on silica gel using hexanes/ethyl acetate 4/1.

Example 24B1-[adamantan-1-yl]-4-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide

The title compound was prepared by substituting EXAMPLE 24A for2-formylphenylboronic acid in EXAMPLE 40A, except here product waspurified by preparative HPLC using a C18 column, 250×50 mm, 10μ, andeluting with a gradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acidin water, giving the product as a trifluoroacetate salt. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 9.70 (br s, 1H), 8.70 (t, 1H), 8.66 (d,1H), 7.96 (dd, 1H), 7.89 (br s, 1H), 7.80 (d, 2H), 7.63 (br s, 1H), 7.50(br s, 2H), 7.32 (m, 6H), 7.19 (m, 6H), 6.98 (d, 2H), 4.15 (br s, 1H)3.80 (m, 4H), 3.40, (m, 4H), 3.25 (m, 4H), 2.97 (br s, 1H), 2.00, 1.80,1.60 (all m, total 18H), 1.24 (m, 4H).

Example 254-(4-{2-[2-(adamantan-1-yl)-6-methylimidazo[1,2-a]pyridin-8-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.05 (s, 1H), 8.55-8.74(m, 3H), 8.07 (s, 1H), 7.93 (dd, 1H), 7.73 (d, 2H), 7.55-7.71 (m, 4H),7.48 (d, 1H), 7.29 (d, 1H), 6.86 (d, 2H), 3.81-3.89 (m, 4H), 3.31-3.38(m, 2H), 3.22-3.30 (m, 2H), 2.42 (s, 3H), 2.03 (s, 3H), 1.91 (d, 8H),1.56-1.77 (m, 10H), 1.20-1.32 (m, 3H). MS (ESI) m/e 856 (M−H)⁻.

Example 26N-(adamantan-2-yl)-6-methyl-8-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}imidazo[1,2-a]pyridine-2-carboxamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.10 (s, 1H), 8.75 (s,1H), 8.62-8.69 (m, 2H), 8.57 (s, 1H), 7.88-7.98 (m, 2H), 7.81 (d, J=8.9Hz, 2H), 7.67-7.73 (m, 1H), 7.60-7.67 (m, 2H), 7.46-7.52 (m, 1H),7.26-7.33 (m, 2H), 6.97 (d, J=9.2 Hz, 2H), 4.25 (s, 2H), 3.80-3.91 (m,4H), 3.35 (t, J=6.4 Hz, 3H), 3.16-3.31 (m, 6H), 2.40 (s, 3H), 1.85-2.02(m, 3H), 1.82 (s, 2H), 1.76 (s, 1H), 1.54-1.71 (m, 8H), 1.45 (d, J=12.6Hz, 2H), 1.19-1.33 (m, 2H). MS (ESI) m/e 856 (M−H)⁻.

Example 274-(4-{2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 27A 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yltrifluoromethanesulfonate

The title compound was prepared by substituting (1R)-(+)-nopinone fortricyclo[5.2.1.02,6]decan-8-one in EXAMPLE 23D.

Example 27B 2-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-benzaldehyde

The title compound was prepared by substituting EXAMPLE 27A for EXAMPLE23D in EXAMPLE 23E.

Example 27C4-(4-{2-[6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 27B for EXAMPLE23E in EXAMPLE 23F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.94 (brs, 1H), 8.63 (t, 1H), 8.62 (d, 1H), 7.93 (dd, 1H), 7.74 (d, 2H),7.47-7.35 (m, 2H), 7.24 (m, 2H), 7.03 (m, 1H), 6.92 (d, 2H), 5.55 (1H),3.85 (dd, 2H), 3.63-3.41 (m, 2H), 3.37-3.23 (m, 8H), 2.41 (m, 2H),2.37-2.29 (m, 4H), 2.15 (m, 2H), 1.91 (s, 3H), 1.62 (d, 2H), 1.40 (d,1H), 1.30 (s, 3H), 1.26 (m, 4H), 0.98 (s, 3H).

Example 28N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamideExample 28A 5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yltrifluoromethanesulfonate

The title compound was prepared by substituting5,5,6-trimethylbicyclo[2.2.1]heptan-2-one fortricyclo[5.2.1.02,6]decan-8-one in EXAMPLE 23D.

Example 28B

The title compound was prepared by substituting EXAMPLE 28A for EXAMPLE23D in EXAMPLE 23E.

Example 28CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 28B for EXAMPLE23E in EXAMPLE 23F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.93 (brs, 1H), 8.60 (m, 2H), 7.93 (d, 1H), 7.74 (d, 2H), 7.44 (m, 1H),7.27-7.17 (m, 4H), 6.90 (d, 2H), 6.20 (br s, 1H), 3.85 (dd, 2H), 3.56(m, 2H), 3.36-3.23 (m, 8H), 2.62 (br s, 2H), 2.42 (br s, 2H), 1.91 (brs, 3H), 1.82 (d, 2H), 1.62 (dd, 2H), 1.52 (d, 1H), 1.28 (m, 5H),1.04-1.00 (m, 6H), 0.90 (s, 3H).

Example 29N-cyclooctyl-5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-2-furamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.10 (s, 1H), 9.21 (s,1H), 8.63-8.72 (m, 2H), 8.29 (d, 1H), 7.90-7.99 (m, 2H), 7.81 (d, 1H),7.55-7.63 (m, 2H), 7.50 (t, 1H), 7.43 (d, 1H), 7.30 (d, 1H), 7.22 (d,1H), 7.05 (d, 2H), 4.64 (s, 2H), 3.93-4.17 (m, 3H), 3.81-3.90 (m, 2H),3.77 (s, 2H), 3.33-3.38 (m, 4H), 3.22-3.30 (m, 4H), 1.92 (s, 1H),1.43-1.79 (m, 14H), 1.18-1.39 (m, 3H). MS (ESI) m/e 811 (M−H).

Example 30N-benzyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.11 (s, 1H), 10.06 (s,1H), 8.85 (s, 1H), 8.60-8.69 (m, 2H), 7.93 (dd, J=9.1, 2.0 Hz, 1H), 7.79(d, J=8.9 Hz, 1H), 7.37-7.51 (m, 3H), 7.28 (d, J=9.5 Hz, 1H), 7.18-7.25(m, 1H), 7.01-7.12 (m, 3H), 6.97 (d, J=9.2 Hz, 2H), 6.85 (d, J=6.8 Hz,2H), 6.12 (d, J=2.8 Hz, 1H), 4.79 (d, J=10.1 Hz, 1H), 4.14-4.30 (m, 2H),4.07 (dd, J=14.9, 6.0 Hz, 2H), 3.77-3.87 (m, 2H), 3.30-3.36 (m, 2H),3.18-3.29 (m, 4H), 3.14 (s, 2H), 2.83-2.98 (m, 2H), 2.74 (d, J=11.7 Hz,1H), 2.61 (t, J=3.2 Hz, 1H), 2.07-2.19 (m, 1H), 1.82-1.97 (m, 1H),1.70-1.80 (m, 1H), 1.54-1.69 (m, 2H), 1.18-1.37 (m, 4H), 1.10 (s, 3H),0.92 (s, 3H). MS (ESI) m/e 845 (M−H)⁻.

Example 314-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 31A Ethyl4-(4-(2-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)benzyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one for2-formylphenylboronic acid and EXAMPLE 16B for EXAMPLE 23C in EXAMPLE40A.

Example 31B4-(4-(2-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)benzyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 31A for EXAMPLE2A in EXAMPLE 2B.

Example 31C4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 31B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 9.42 (s, 1H), 8.64 (m, 2H),7.93 (dd, 1H), 7.76 (m, 2H), 7.28 (d, 1H), 7.17 (m, 1H), 6.96 (m, 3H),6.63 (s, 1H), 3.84 (m, 5H), 3.26 (m, 15H), 2.67 (d, 3H), 2.29 (m, 8H),1.90 (m, 2H), 1.59 (m, 2H), 1.24 (m, 2H).

Example 32N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzyl)piperazin-1-yl]benzamideExample 32A2-((1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzonitrile

2-Fluorobenzonitrile (100 mg),(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (380 mg),triethylamine (1.5 mL) were dissolved in anhydrous dimethylsulfoxide (5mL) and heated at 130° C. overnight. The reaction mixture was cooled toroom temperature, and diluted with ethyl acetate. The organic phase waswashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column purification with0-5% methanol/dichloromethane to afford the title compound.

Example 32B2-((1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzaldehyde

EXAMPLE 32A (80 mg) was dissolved in anhydrous dichloromethane (5 mL).The solution was cooled at 0° C., and diisobutylaluminum hydride 1M indichloromethane solution (0.7 mL) was added. The reaction mixture wasstirred at room temperature for 3 hours. The reaction was quenched withmethanol and 5% L-tartaric acid aqueous solution. The solution wasextracted with ethyl acetate, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column purification with0-30% ethyl acetate in hexane to afford the title compound.

Example 32C Ethyl4-(4-(2-((1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 32B for2-formylphenylboronic acid and ethyl 4-(piperazin-1-yl)benzoate forEXAMPLE 23C in EXAMPLE 40A.

Example 32D4-(4-(2-((1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 32C for EXAMPLE2A in EXAMPLE 2B.

Example 32EN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzyl)piperazin-1-yl]benzamide

The title compound was prepared by substituting EXAMPLE 32D for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.10 (s, 1H), 8.65 (m, 2H),7.93 (dd, 1H), 7.78 (d, 2H), 7.26 (m, 3H), 7.00 (d, 2H), 6.73 (d, 1H),6.64 (t, 1H), 4.26 (m, 1H), 3.83 (dd, 2H), 3.65 (m, 2H), 3.25 (m, 14H),2.63 (m, 1H), 2.32 (d, 1H), 2.13 (m, 1H), 1.88 (m, 3H), 1.60 (m, 2H),1.48 (m, 1H), 1.26 (m, 5H), 1.07 (m, 6H).

Example 334-(4-{2-[3-azabicyclo[3.2.2]non-3-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 33A 2-(3-azabicyclo[3.2.2]nonan-3-yl)benzaldehyde

The title compound was prepared by substituting 2-fluorobenzaldehyde for2-fluorobenzonitrile and (1s,5s)-3-azabicyclo[3.2.2]nonane for(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine in EXAMPLE32A.

Example 33B Ethyl4-(4-(2-(3-azabicyclo[3.2.2]nonan-3-yl)benzyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 33A for2-formylphenylboronic acid and ethyl 4-(piperazin-1-yl)benzoate forEXAMPLE 23C in EXAMPLE 40A.

Example 33C4-(4-(2-(3-azabicyclo[3.2.2]nonan-3-yl)benzyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 33B for EXAMPLE2A in EXAMPLE 2B.

Example 33D4-(4-{2-[3-azabicyclo[3.2.2]non-3-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 33C for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.07 (m, 1H), 8.65 (m, 2H),7.93 (dd, 1H), 7.79 (d, 2H), 7.56 (d, 1H), 7.44 (d, 2H), 7.26 (m, 2H),7.00 (d, 2H), 4.48 (s, 2H), 4.01 (s, 2H), 3.83 (dd, 2H), 3.28 (m, 10H),2.98 (d, 4H), 1.90 (m, 7H), 1.62 (m, 6H), 1.25 (m, 2H).

Example 34N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[tricyclo[4.3.1.1³,⁸]undec-4-en-4-yl]benzyl}piperazin-1-yl)benzamideExample 34Atricyclo[4.3.1.1^(3,8)]undec-4-en-4-yltrifluoromethanesulfonate

The title compound was prepared by substitutingtricyclo[4.3.1.1^(3,8)]undecan-4-one for tricyclo[5.2.1.02,6]decan-8-onein EXAMPLE 23D.

Example 34B 2-Tricyclo[4.3.1.1^(3,8)]undec-4-en-4-yl-benzaldehyde

The title compound was prepared by substituting EXAMPLE 34A for EXAMPLE23D in EXAMPLE 23E.

Example 34CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[tricyclo[4.3.1.1^(3,8)]undec-4-en-4-yl]benzyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 34B for EXAMPLE23E in EXAMPLE 23F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.97 (brs, 1H), 8.65 (t, 1H), 8.62 (d, 1H), 7.93 (dd, 1H), 7.74 (d, 2H), 7.41(m, 1H), 7.28-7.21 (m, 3H), 7.08 (m, 1H), 6.92 (d, 2H), 5.52 (m, 1H),3.84 (dd, 2H), 3.54 (m, 2H), 3.37-3.24 (m, 8H), 2.57-2.44 (m, 2H),2.29-2.09 (m, 4H), 1.94-1.84 (m, 2H), 1.91 (s, 3H), 1.62 (d, 2H),1.36-1.18 (m, 4H), 0.88 (s, 9H).

Example 357,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-phenylbicyclo[2.2.1]hept-2-ene-1-carboxamide

¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.14 (s, 1H), 9.63 (s,1H), 9.35 (s, 1H), 8.68 (t, 1H), 8.65 (d, 1H), 7.94 (dd, 1H), 7.80 (d,2H), 7.53-7.60 (m, 1H), 7.33-7.41 (m, 2H), 7.30 (d, 1H), 7.20-7.27 (m,3H), 7.07 (t, 1H), 7.01 (d, 2H), 6.18 (d, 1H), 4.77 (s, 1H), 4.38 (d,1H), 4.07 (s, 2H), 3.85 (dd, 3H), 3.32-3.37 (m, 4H), 3.22-3.30 (m, 4H),3.07-3.20 (m, 2H), 2.71-2.84 (m, 1H), 2.65 (t, 1H), 2.12-2.25 (m, 1H),1.85-1.96 (m, 1H), 1.74-1.82 (m, 1H), 1.56-1.66 (m, 2H), 1.20-1.34 (m,4H), 1.17 (s, 3H), 1.00-1.05 (m, 3H). MS (ESI) m/e 831 (M−H)⁻.

Example 367,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]bicyclo[2.2.1]hept-2-ene-1-carboxamide

¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.11 (s, 1H), 10.24 (s,1H), 8.57-8.73 (m, 2H), 8.00 (d, 1H), 7.94 (dd, J=9.2, 2.1 Hz, 1H), 7.80(d, 2H), 7.50 (dd, 1H), 7.33-7.43 (m, 2H), 7.30 (d, 1H), 7.20 (dd, 1H),7.01 (d, 2H), 6.14 (d, 1H), 4.87 (d, 1H), 4.21-4.29 (m, 1H), 4.06-4.20(m, 4H), 3.84 (dd, 4H), 3.51-3.59 (m, 2H), 3.35 (t, 2H), 3.21-3.31 (m,4H), 3.01-3.20 (m, 2H), 2.94 (d, 1H), 2.63 (t, 1H), 2.53-2.61 (m, 1H),2.20-2.29 (m, 1H), 2.08-2.19 (m, 2H), 1.80 (t, 2H), 1.58-1.73 (m, 4H),1.51-1.59 (m, 1H), 1.20-1.33 (m, 6H), 1.17 (s, 3H), 1.10-1.15 (m, 4H),0.94 (s, 3H), 0.86 (s, 3H), 0.47 (d, 3H). MS (ESI) m/e 891 (M−H)⁻.

Example 37N-(adamantan-1-ylmethyl)-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide

¹H NMR (500 MHz, dimethylsulfoxide-d₆) 3 ppm 12.14 (s, 1H), 10.53 (s,1H), 8.68 (t, 1H), 8.64 (d, 1H), 8.17 (s, 1H), 7.94 (dd, 1H), 7.82 (t,1H), 7.47 (d, 1H), 7.40 (t, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 7.23 (d,1H), 6.13 (d, 1H), 4.88 (d, 1H), 4.11-4.22 (m, 3H), 3.84 (dd, 2H), 3.56(d, 1H), 3.22-3.29 (m, 4H), 3.14-3.22 (m, 2H), 2.88-3.03 (m, 2H), 2.80(dd, 1H), 2.62-2.68 (m, 1H), 2.53-2.63 (m, 1H), 2.08-2.18 (m, 1H),1.84-1.96 (m, 1H), 1.68 (s, 4H), 1.62 (d, 2H), 1.48 (d, 3H), 1.34 (d,3H), 1.20-1.30 (m, 4H), 1.10-1.19 (m, 6H), 1.00-1.07 (m, 3H), 0.97 (s,3H). MS (ESI) m/e 903 (M−H)⁻.

Example 38N-cyclopropyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide

¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.15 (s, 1H), 10.14 (s,1H), 8.68 (t, 1H), 8.64 (d, 1H), 8.04 (s, 1H), 7.94 (dd, 1H), 7.80 (d,2H), 7.53 (dd, 1H), 7.35-7.43 (m, 2H), 7.30 (d, 1H), 7.12-7.17 (m, 1H),6.99-7.05 (m, 2H), 6.10 (d, 1H), 4.82 (d, 1H), 4.27 (d, 1H), 4.13 (t,2H), 3.85 (dd, 2H), 3.35 (t, 2H), 3.16-3.30 (m, 6H), 3.09 (s, 2H), 2.60(t, 1H), 2.52-2.58 (m, 1H), 2.43-2.49 (m, 1H), 2.03-2.14 (m, 1H),1.85-1.97 (m, 1H), 1.62 (d, 3H), 1.17-1.32 (m, 3H), 1.14 (s, 3H), 0.91(s, 3H), 0.45-0.58 (m, 2H), 0.37-0.45 (m, 1H), 0.11-0.19 (m, 1H). MS(ESI) m/e 795 cm-H)⁻.

Example 397,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxylicacid

¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 11.96 (s, 1H), 8.57-8.66(m, 2H), 7.92 (dd, 1H), 7.73 (d, 2H), 7.46-7.51 (m, 1H), 7.40-7.46 (m,1H), 7.26 (d, 1H), 7.11-7.22 (m, 4H), 7.06 (d, 2H), 7.00 (dd, 1H), 6.91(d, 2H), 6.26 (d, 1H), 6.16 (d, 1H), 5.10 (s, 1H), 4.59 (s, 1H), 3.83(dd, 2H), 3.65-3.73 (m, 1H), 3.38-3.52 (m, 3H), 3.23 (s, 2H), 2.50-2.56(m, 4H), 2.26-2.42 (m, 2H), 1.98-2.07 (m, 2H), 1.90 (s, 3H), 1.46-1.66(m, 4H), 1.19-1.31 (m, 4H), 1.14 (s, 3H), 1.11 (s, 3H), 1.01-1.10 (m,2H), 0.93 (s, 6H). MS (ESI) m/e 757

Example 404-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 40A2-((4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenyl)piperazin-1-yl)methyl)phenylboronicacid

EXAMPLE 23C (151 mg) and 2-formylphenylboronic acid (54 mg) werecombined in a mixture of tetrahydrofuran (3.5 mL) and acetic acid (1.1mL). Sodium cyanoborohydride resin (252 mg of 2.38 mmol/g resin) wasadded and the reaction was stirred at room temperature overnight. Thereaction mixture was quenched with aqueous NaHCO₃ solution and extractedwith dichloromethane. The organic layer was washed thoroughly with waterand with brine, dried over MgSO₄, filtered, and concentrated undervacuum. The crude material was then triturated with ether to afford thetitle compound.

Example 40B4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamidenitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenoxybenzamide

EXAMPLE 40A (45 mg),8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane hydrochloride(27 mg), bis(triphenylphosphine)palladium(II) dichloride (5 mg), andlithium hydroxide (7 mg) were combined in a mixture of dimethoxyethane(1.6 mL), methanol (0.5 mL) and water (0.7 mL) in a microwave vial. Thereaction mixture was heated in a CEM Discover microwave reactor at 150°C. for 15 minutes. The crude material was purified by preparative HPLCusing a C18 column, 250×21.20 mm, 5μ, and eluting with a gradient of20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.79 (br s, 1H), 8.51 (d, 1H), 8.41 (t, 1H),7.90 (dd, 1H), 7.73 (m, 4H), 7.60 (d, 2H), 7.41 (m, 2H), 7.35 (m, 1H),6.81 (m, 2H), 3.83 (dd, 2H), 3.65 (s, 2H), 3.51 (s, 2H), 3.17 (m, 4H),3.08 (m, 4H), 2.45 (m, 6H), 1.92 (m, 2H), 1.62 (m, 4H), 1.54 (m, 3H),1.38 (m, 6H).

Example 414-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 41A 3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)benzenesulfonamide

The title compound was prepared by substitutingtetrahydro-2H-pyran-4-amine for cyclohexylmethylamine in EXAMPLE 2D.

Example 41B 4-{-4-[adamantan-1-ylcarbonyl]piperazin-1-yl}benzoic acid

The title compound was prepared by substituting EXAMPLE 10B for EXAMPLE8D in EXAMPLE 8E.

Example 41C4-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 41B for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.05 (br s, 1H), 8.64 (d, 1H), 8.30 (d, 1H),7.95 (dd, 1H), 7.56 (d, 2H), 7.38 (d, 1H), 6.95 (d, 2H), 3.94 (m, 1H),3.76 (m, 2H), 3.70 (m, 4H), 3.45 (m, 2H), 3.29 (m, 4H), 1.90 (m, 11H),1.65 (m, 8H).

Example 424-{4-[adamantan-2-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 42A ethyl 4-{-4-[adamantan-2-ylcarbonyl]piperazin-1-yl}benzoate

The title compound was prepared by substituting EXAMPLE 10A for EXAMPLE8B and adamantane-2-carboxylic acid for adamantane-1-carboxylic acid inEXAMPLE 8F.

Example 42B 4-{-4-[adamantan-2-ylcarbonyl]piperazin-1-yl}benzoic acid

The title compound was prepared by substituting EXAMPLE 42A for EXAMPLE8D in EXAMPLE 8E.

Example 42C4-{4-[adamantan-2-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 42B for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.05 (br s, 1H), 8.64 (d, 1H), 8.30 (d, 1H),7.95 (dd, 1H), 7.56 (d, 2H), 7.38 (d, 1H), 6.95 (d, 2H), 3.94 (m, 1H),3.76 (m, 2H), 3.70 (m, 4H), 3.45 (m, 2H), 3.29 (m, 4H), 2.86 (s, 1H),2.22 (s, 1H), 2.18 (s, 1H), 1.90 (m, 5H), 1.78 (m, 5H), 1.65 (m, 4H),1.50 (m, 2H).

Example 434-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 43A4-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}benzoicacid

The title compound was prepared by substituting EXAMPLE 11C for EXAMPLE8D in EXAMPLE 8E.

Example 43B4-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 43A for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.94 (br s, 1H), 8.64 (d, 1H), 8.30 (d, 1H),7.95 (dd, 1H), 7.76 (d, 2H), 7.38 (d, 1H), 6.62 (d, 2H), 5.03 (v br s,1H), 4.63 (s, 1H), 3.87 (m, 3H), 3.61 (br s, 1H), 3.48 (m, 2H), 3.30 (m,2H), 3.04 (d, 1H), 1.90 (m, 8H), 1.80 (m, 5H), 1.60 (m, 8H).

Example 444-{1S,5S)-3-[adamantan-1-ylcarbonyl]-3,6-diazabicyclo[3.2.0]hept-6-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 44A (1S,5S)-benzyl6-(4-(ethoxycarbonyl)phenyl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The title compound was prepared by substituting (1S,5S)-benzyl3,6-diazabicyclo[3.2.0]heptane-3-carboxylate 4-methylbenzenesulfonatefor benzyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate in EXAMPLE 8A.

Example 44B ethyl 4-((1R,5S)-3,6-diazabicyclo[3.2.0]heptan-6-yl)benzoate

The title compound was prepared by substituting EXAMPLE 44A for EXAMPLE8A in EXAMPLE 8B.

Example 44C ethyl4-[(1S,58)-3-(adamantan-1-ylcarbonyl)-3,6-diazabicyclo[3.2.0]hept-6-yl]benzoate

The title compound was prepared by substituting EXAMPLE 44B for EXAMPLE8B in EXAMPLE 8C.

Example 44D4-[(1S,5S)-3-(adamantan-1-ylcarbonyl)-3,6-diazabicyclo[3.2.0]hept-6-yl]benzoicacid

The title compound was prepared by substituting EXAMPLE 44C for EXAMPLE8D in EXAMPLE 8E.

Example 44E4-{(1S,5S)-3-[(1s,3R,5S)-adamantan-1-ylcarbonyl]-3,6-diazabicyclo[3.2.0]hept-6-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 44D for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.94 (br s, 1H), 8.64 (d, 1H), 8.30 (d, 1H),7.95 (dd, 1H), 7.56 (d, 2H), 7.38 (d, 1H), 4.71 (t, 1H), 4.29 (d, 1H),4.20 (d, 1H), 3.97 (m, 2H) 3.86 (m, 2H), 3.48 (m, 3H), 3.21 (m, 2H),3.11 (m, 1H), 1.85 (m, 6H), 1.76 (m, 6H), 1.60 (m, 7H).

Example 45N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamideExample 45A ethyl 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate

Ethyl 4-fluorobenzoate (11.65 g, 69.3 mmol),1,4-dioxa-8-azaspiro[4.5]decane (9.92 g, 69.3 mmol), and triethylamine(9.66 mL, 69.3 mmol) in N,N-dimethylacetamide (80 mL) were stirred at80° C. for 24 hours. The reaction was cooled, poured into ethyl acetate,washed with 3× water and brine, and concentrated to afford the titlecompound.

Example 45B ethyl 4-(4-oxopiperidin-1-yl)benzoate

EXAMPLE 45A (20 g, 68 mmol) was stirred at 90° C. for 24 hours in amixture of dioxane (200 mL), acetic acid (70 mL) and water (150 mL). Thereaction mixture was concentrated, and partitioned between ethyl acetateand water. The organic layer was washed with brine and concentrated. Theresidue was chromatographed on silica gel using 20% ethyl acetate inhexanes to afford the title compound.

Example 45C ethyl4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)cyclohexyl)benzoate

EXAMPLE 45B (2.72 g, 11 mmol) and(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (1.69 g, 11mmol) were refluxed for 24 hours in toluene (50 mL) under a Dean-Starktrap. The resulting mixture was cooled and ethanol (50 mL) was added,followed by the portionwise addition of NaBH₄ (2.0 g). The mixture wasstirred for 30 minutes, and water was added. The solution was extractedthree times with ether, and the combined extracts were washed with waterand brine, and concentrated. The residue was chromatographed on silicagel using ethyl acetate to afford the title compound.

Example 45D ethyl4-(4-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)amino)cyclohexyl)benzoate

The title compound was prepared as described in EXAMPLE 7A using EXAMPLE45C in place of EXAMPLE 6C.

Example 45E4-(4-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)amino)cyclohexyl)benzoicacid

The title compound was prepared as described in EXAMPLE 2B using EXAMPLE45D in place of EXAMPLE 2A.

Example 45FN-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE45E in place of EXAMPLE 1A and EXAMPLE 41A in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (s, 1H), 8.54 (s, 1H), 8.14 (d, 1H), 7.89(d, 1H), 731 (d, 2H), 7.10-7.30 (m, 6H), 6.84 (d, 2H), 3.87 (m, 4H),3.47 (t, 2H), 3.07 (m, 2H), 2.75 (m, 2H), 2.52 (m, 2H), 2.19 (m, 2H),1.78-1.99 (m, 6H), 1.53-1.75 (m, 7H), 1.27 (m, 2H), 1.17 (m, 2H), 1.15(s, 3H), 1.00 (m, 2H), 0.94 (s, 3H), 0.76 (d, 2H).

Example 46N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamideExample 46A ethyl4-(4-(3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propanamido)cyclohexyl)benzoate

To a solution of EXAMPLE 45C (192 mg, 0.5 mmol), triethylamine (0.077mL, 0.55 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) intetrahydrofuran (5 mL) was added 3-phenylpropanoyl chloride (0.082 mL,0.55 mmol), and the reaction was stirred for 24 hours. The residue waschromatographed on silica gel using 20-50% ethyl acetate in hexanes toafford the title compound.

Example 46B4-(4-(3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propanamido)cyclohexyl)benzoicacid

The title compound was prepared as described in EXAMPLE 2B using EXAMPLE46A in place of EXAMPLE 2A.

Example 46CN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE46B in place of EXAMPLE 1B and EXAMPLE 2D in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (s, 1H), 8.61 (m, 2H), 7.92 (d, 1H), 7.72(d, 2H), 7.20 (m, 5H), 6.90 (m, 2H), 4.07 (m, 4H), 3.93 (m, 2H), 3.18(m, 4H), 2.65-2.95 (m, 6H), 2.08 (m, 2H), 1.91 (m, 2H), 1.78-1.99 (m,6H), 1.55-1.76 (m, 11H), 1.22 (s, 3H), 1.17 (m, 2H), 1.01 (s, 3H), 0.99(d, 2H), 0.90 (d, 2H).

Example 474-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 10D for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.05 (br s,1H), 8.82 (br s, 1H), 8.62 (m, 2H), 7.96 (dd, 1H), 7.78 (d, 2H), 7.26(d, 1H), 7.00 (d, 2H), 3.86 (br s, 1H), 3.55 (br s, 2H), 3.30 (m, 8H),2.96 (br s, 1H), 1.99 (s, 3H), 1.60 (m, 18H), 1.18 (m, 3H), 1.00 (m,2H).

Example 486-{3-[adamantan-1-yl]-4-hydroxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide

The title compound was prepared by substituting6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid forEXAMPLE 1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide inEXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.57 (br s, 1H),9.52 (s, 1H), 8.68 (d, 1H), 8.61 (m, 1H), 8.54 (s, 1H), 8.27-8.21 (m,1H), 8.14 (s, 1H), 8.07 (d, 1H), 8.02-7.95 (m, 3H), 7.56-7.47 (m, 2H),7.25 (d, 1H), 6.91 (d, 1H), 2.16 (br s, 6H), 2.07 (br s, 4H), 1.76-1.65(m, 12H), 1.25-1.13 (m, 4H), 1.01 (t, 2H).

Example 494-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 49A ethyl4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)benzoate

Ethyl 4-(piperazin-1-yl)benzoate (100 mg), 1-admantyl bromomethyl ketone(110 mg) and sodium carbonate (46 mg) were suspended in anhydrousacetonitrile (2 mL). The reaction mixture was stirred at roomtemperature overnight. The reaction was quenched with saturated NaHCO₃aqueous solution, and extracted with ethyl acetate. The organic phasewas washed with water, brine, dried over Na₂SO₄, filtered andconcentrated to afford the title compound

Example 49B 4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 49A for EXAMPLE2A in EXAMPLE 2B.

Example 49C4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 49B for EXAMPLE1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.16 (m, 1H), 8.65 (m, 2H),7.94 (dd, 1H), 7.81 (d, 2H), 7.26 (d, 1H), 7.02 (d, 2H), 4.58 (s, 2H),4.01 (s, 2H), 3.29 (m, 10H), 1.71 (m, 18H), 1.17 (m, 3H), 1.00 (m, 2H).

Example 504-{[adamantan-2-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 50A 4-[(Adamantan-1-ylmethyl)-amino]-benzoic acid ethyl ester

Ethyl 4-fluorobenzoate (336 mg), (2-adamantylmethyl)amine hydrochloride(504 mg) and sodium carbonate (636 mg) were combined indimethylsulfoxide (5 mL). The reaction was heated to 130° C. overnight.The reaction mixture was diluted with ethyl acetate, poured into water,and the organic layer was washed thoroughly with water and with brine.The combined organic layers were dried over MgSO₄, filtered andconcentrated under vacuum. The crude material was purified by flashchromatography eluting with 9/1 hexanes/ether.

Example 50B 4-[(Adamantan-1-ylmethyl)-amino]-benzoic acid

EXAMPLE 50A (365 mg) was dissolved in tetrahydrofuran (6 mL), methanol(2 mL) and water (2 mL). The reaction was heated to 60° C. overnight.The solution was then acidified with 1M aqueous HCl solution. Theproduct was collected by filtration and dried under vacuum.

Example 50C4-{[adamantan-2-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 50B for EXAMPLE1A and EXAMPLE 41A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.80 (s, 1H), 8.64 (d, 1H),8.29 (d, 1H), 7.94 (dd, 1H), 7.62 (d, 2H), 7.38 (d, 1H), 6.57 (m, 3H),3.94 (m, 1H), 3.87 (m, 2H), 3.47 (m, 2H), 3.17 (t, 2H), 1.91 (m, 6H),1.81 (m, 5H), 1.65 (m, 6H), 1.50 (d, 2H).

Example 514-{2-[adamantan-1-yl]ethoxy}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 51A 4-(2-adamantan-1-yl-ethoxy)-benzoic acid ethyl ester

Ethyl 4-hydroxybenzoate (83 mg) and 1-adamantaneethanol (90 mg) werecombined in tetrahydrofuran (2 mL). Polymer-supported triphenylphospine(250 mg of 3 mmol/g) and di-tert-butyl azodicarboxylate (173 mg) wereadded. The reaction was stirred at room temperature overnight. The resinwas removed by filtration through celite. The filtrate was concentratedunder vacuum, and the residue was triturated with 95/5 hexanes/ether toafford the title compound.

Example 51B 4-(2-adamantan-1-yl-ethoxy)-benzoic acid

The title compound was prepared by substituting EXAMPLE 51A for EXAMPLE50A in EXAMPLE 50B.

Example 51C4-{2-[adamantan-1-yl]ethoxy}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 51B for EXAMPLE1A and EXAMPLE 41A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 12.25 (s, 1H), 8.65 (d, 1H),8.30 (d, 1H), 7.95 (dd, 1H), 7.83 (d, 2H), 7.40 (d, 1H), 7.00 (d, 2H),4.09 (t, 2H), 3.95 (m, 1H), 3.87 (m, 2H), 3.47 (m, 2H), 1.92 (m, 5H),1.64 (m, 8H), 1.54 (d, 6H), 1.52 (t, 2H).

Example 52

N³-[adamantan-1-ylacetyl]-N³-benzyl-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-beta-alaninamide

Example 52A 3-[(2-adamantan-1-yl-acetyl)-benzyl-amino]-propionic acidethyl ester

The title compound was prepared by substituting 1-adamantaneacetic acidfor EXAMPLE 1A and ethyl 3-(benzylamino)propanoate for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.

Example 52B 3-[(2-adamantan-1-yl-acetyl)-benzyl-amino]-propionic acid

The title compound was prepared by substituting EXAMPLE 52A for EXAMPLE2A in EXAMPLE 2B.

Example 52C

N³-[adamantan-1-ylacetyl]-N³-benzyl-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-beta-alaninamide

The title compound was prepared by substituting EXAMPLE 52B for EXAMPLE1A, and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.12 (br s, 1H), 8.66 (t, 1H),8.56 (d, 1H), 7.86 (m, 1H), 7.37-7.21 (m, 4H), 7.09 (t, 2H), 4.45 (s,1H), 4.34 (s, 1H), 3.39 (t, 1H), 2.47 (t, 1H), 1.97 (s, 2H), 1.86 (m,3H), 1.78-1.52 (m, 18H), 1.24 (s, 1H), 1.22-1.12 (m, 6H), 0.98 (m, 2H).

Example 53N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamideExample 53A ethyl 4-(bis(2-hydroxyethyl)amino)benzoate

The title compound was prepared by the methods described in Soloway, A.H., Nyilas, E., J. Org. Chem. 26, 1091 (1961).

Example 53B ethyl 4-(bis(2-(methylsulfonyloxy)ethyl)amino)benzoate

EXAMPLE 53A (506 mg) was dissolved in dichloromethane (10 mL) and themixture was cooled to −14° C. (acetone-ice bath). Triethylamine (0.83mL) was added, followed by the addition of methanesulfonyl chloride(0.46 mL) dropwise, keeping the temperature below 2° C. The acetone-icebath was removed and reaction continued at room temperature undernitrogen for 3.5 hours. The reaction was partitioned between saturatedaqueous NaHCO₃ and ether. The organic layer was washed twice with 1MH₃PO₄, and crystals formed in the organic layer. The mixture wasfiltered and the solid material was washed with ether and dried to givethe product.

Example 53C ethyl4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)piperazin-1-yl)benzoate

EXAMPLE 53B (409 mg) was dissolved in acetonitrile (10 mL), then(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (0.17 mL),potassium carbonate (375 mg), and lithium bromide (183 mg) were added.The reaction was heated under reflux overnight. The reaction was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with brine and dried over sodium sulfate. The mixture wasfiltered and the crude material was purified by column chromatography onsilica gel using 85/15 hexanes/ethyl acetate.

Example 53D4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 53C for EXAMPLE8D in EXAMPLE 8E.

Example 53EN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamide

The title compound was prepared by substituting EXAMPLE 53D for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.15 (br s,1H), 9.40 (br s, 1H), 8.62 (m, 2H), 7.96 (dd, 1H), 7.80 (d, 2H), 7.26(d, 1H), 7.03 (d, 2H), 4.14 (br s, 2H), 3.72 (br m, 2H), 3.28 (t, 2H),3.17 (br m, 4H), 2.30 (m, 3H), 2.00 (m, 2H), 1.83 (m, 1H), 1.70 (m, 6H),1.20 (m, 8H), 1.07 (m, 4H), 0.95 (s, 3H).

Example 544-{4-[adamantan-1-yl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 54A ethyl 4-[4-(adamantan-1-yl)piperazin-1-yl]benzoate

The title compound was prepared by substituting adamantane-1-aminehydrochloride for(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine in EXAMPLE53C.

Example 54B 4-[4-(adamantan-1-yl)piperazin-1-yl]benzoic acid

The title compound was prepared by substituting EXAMPLE 54A for EXAMPLE8D in EXAMPLE 8E.

Example 54C4-{-4-[adamantan-1-yl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 54B for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.10 (br s,1H), 9.18 (br s, 1H), 8.62 (m, 2H), 7.96 (dd, 1H), 7.80 (d, 2H), 7.24(d, 1H), 7.03 (d, 2H), 4.09 (br d, 2H), 3.65 (br m, 2H), 3.28 (t, 2H),3.10 (br m, 4H), 2.20 (s, 3H), 1.95 (s, 6H), 1.70 (m, 12H), 1.18 (m,3H), 1.00 (m, 2H).

Example 55N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[3,5-dimethyladamantan-1-yl]piperazin-1-yl}benzamideExample 55A ethyl4-[4-(3,5-dimethyladamantan-1-yl)piperazin-1-yl]benzoate

The title compound was prepared by substituting3,5-dimethyladamantane-1-amine hydrochloride for(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine in EXAMPLE53C.

Example 55B 4-[4-(3,5-dimethyladamantan-1-yl)piperazin-1-yl]benzoic acid

The title compound was prepared by substituting EXAMPLE 55A for EXAMPLE8D in EXAMPLE 8E.

Example 55CN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{-4-[3,5-dimethyladamantan-1-yl]piperazin-1-yl}benzamide

The title compound was prepared by substituting EXAMPLE 55B for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.10 (v brs, 1H), 9.18 (v br s, 1H), 8.62 (m, 2H), 7.96 (dd, 1H), 7.80 (d, 2H),7.24 (d, 1H), 7.03 (d, 2H), 4.07 (br s, 2H), 3.62 (br s, 2H), 3.28 (t,2H), 3.10 (br m, 4H), 2.25 (m, 1H), 1.70 (m, 12H), 1.35 (s, 3H), 1.18(m, 6H), 1.00 (m, 2H), 0.89 (s, 6H).

Example 56[(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-3a-yl]methyl(4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)sulfamate

The title compound was prepared by substituting((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-3a-yl)methyl sulfamate for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 7.81 (d, 2H), 7.75 (m, 1H), 7.55 (m, 4H), 7.41(d, 2H), 7.35 (m, 1H), 6.96 (d, 2H), 4.54 (dd, 1H), 4.35 (br s, 1H),4.31 (d, 1H), 4.22 (t, 2H), 4.14 (d, 1H), 3.91 (br s, 2H), 3.72 (m, 2H),3.60 (m, 3H), 3.11 (br s, 2H), 2.91 (br s, 2H), 1.45 (s, 3H), 1.35 (s,3H), 1.14 (d, 6H).

Example 574-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1B using41R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamidein place of 4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.95 (s, 1H), 7.80 (d, 2H), 7.48 (m, 5H), 7.38(m, 2H), 7.27 (d, 1H), 6.93 (d, 2H), 3.77 (d, 1H), 3.42 (m, 3H), 3.24(m, 4H), 2.40 (m, 4H), 2.30 (m, 1H), 2.03 (m, 1H), 1.92 (m, 2H), 1.55(m, 1H), 1.40 (m, 1H), 1.02 (s, 3H), 0.88 (s, 3H).

Example 584-(4-{2-[adamantan-1-yl]ethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 58A ethyl 4-[4-(adamantan-1-ylacetyl)piperazin-1-yl]benzoate

The title compound was prepared by substituting EXAMPLE 10A for EXAMPLE8B and 1-adamantylacetic acid for adamantane-1-carboxylic acid inEXAMPLE 8C.

Example 58B ethyl 4-{4-[2-(adamantan-1-yl)ethyl]piperazin-1-yl}benzoate

The title compound was prepared by substituting EXAMPLE 58A for EXAMPLE8C in EXAMPLE 8D.

Example 58C 4-{4-[2-(adamantan-1-yl)ethyl]piperazin-1-yl}benzoic acid

The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE8D in EXAMPLE 8E.

Example 58D4-(4-{2-[adamantan-1-yl]ethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 58C for EXAMPLE8E in EXAMPLE 8F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.10 (v brs, 1H), 9.44 (v br s, 1H), 8.62 (m, 2H), 7.96 (dd, 1H), 7.80 (d, 2H),7.26 (d, 1H), 7.02 (d, 2H), 4.07 (br s, 2H), 3.60 (br s, 2H), 3.29 (t,2H), 3.10 (m, 6H), 1.95 (s, 3H), 1.65 (m, 12H), 1.45 (m, 8H), 1.18 (m,3H), 1.00 (m, 2H).

Example 594-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1B using((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamidein place of 4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.95 (s, 1H), 7.80 (d, 2H), 7.48 (m, 5H), 7.38(m, 2H), 7.27 (d, 1H), 6.91 (d, 2H), 3.75 (d, 1H), 3.40 (m, 3H), 3.25(m, 4H), 2.40 (m, 4H), 2.30 (m, 1H), 2.03 (m, 1H), 1.91 (m, 2H), 1.50(m, 1H), 1.38 (m, 1H), 1.02 (s, 3H), 0.80 (s, 3H).

Example 60N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-({(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)biphenyl-4-carboxamideExample 60A methyl 4′-formylbiphenyl-4-carboxylate

The title compound was prepared as described in EXAMPLE 4A using4-iodobenzaldehyde in place of 1-bromo-3-iodobenzene.

Example 60B methyl4′-(((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)methyl)biphenyl-4-carboxylate

The title compound was prepared as described in EXAMPLE 7A using(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine in place ofEXAMPLE 6C and EXAMPLE 60A in place of phenylpropanal.

Example 60C methyl4′-((3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propanamido)methyl)biphenyl-4-carboxylate

The title compound was prepared as described in EXAMPLE 46A usingEXAMPLE 60B in place of EXAMPLE 45C.

Example 60D 4′-((3-phenyl-N-((1 S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propanamido)methyl)biphenyl-4-carboxylicacid

The title compound was prepared as described in EXAMPLE 2B using EXAMPLE60C in place of EXAMPLE 2A.

Example 60EN-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-({(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)biphenyl-4-carboxamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE60D in place of EXAMPLE 1A and EXAMPLE 2D in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (s, 1H), 8.63 (d, 1H), 8.59 (m, 1H), 7.94(m, 3H), 7.73 (d, 2H), 7.68 (d, 1H), 7.62 (d, 1H), 7.05-7.26 (m, 7H),4.61 (m, 1H), 4.36 (m, 1H), 2.88 (m, 3H), 2.30 (m, 3H), 1.66 (m, 10H),1.20 (m, 2H), 1.19 (s, 3H), 1.17 (s, 3H), 0.87-1.06 (m, 10H).

Example 61N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidin-1-yl)benzamideExample 61A methyl 4-(4-oxopiperidin-1-yl)benzoate

This EXAMPLE was prepared using methods described by Bruncko, et. al.,J. Med. Chem. 2007, 50, 641-662.

Example 61B methyl 4-(4-(2-bromobenzylidene)piperidin-1-yl)benzoate

Dimethylsulfoxide (22.88 mL) with sodium hydride (0.332 g) was heated to70° C. for 1 hour, the mixture was cooled to room temperature and(2-bromobenzyl)triphenylphosphonium bromide (3.40 g) was added inseveral portions. The reaction mixture was stirred at room temperaturefor 1 hour. A solution of EXAMPLE 61A (1.8 g) in dimethylsulfoxide (5.20mL) was then added and the reaction was heated at 70° C. over theweekend. The reaction mixture was acidified with 1M aqueous HCl solutionand extracted with ether. The organic layer was washed thoroughly withwater and with brine, dried over MgSO₄, filtered and concentrated undervacuum. The crude material was purified by flash chromatography elutingwith 100% hexanes to 20% ethyl acetate in hexanes.

Example 61C4-(4-(2-((1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl)benzylidene)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting(1S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-ylboronic acid for EXAMPLE40A and EXAMPLE 61B for8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane hydrochloridein EXAMPLE 40B.

Example 61DN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 61C for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.97 (s, 1H), 8.64 (m, 2H),7.93 (dd, 1H), 7.74 (d, 2H), 7.30 (d, 1H), 7.21 (m, 2H), 7.14 (m, 1H),6.95 (d, 2H), 6.36 (s, 1H), 5.87 (d, 1H), 3.84 (m, 2H), 3.48 (m, 2H),3.40, 3.32, 3.24 (all m, total 6H), 2.40 (t, 1H), 2.34 (m, 4H), 1.90 (m,2H), 1.61 (m, 3H), 1.27 (m, 3H), 1.06 (m, 1H), 0.94 (s, 3H), 0.83 (s,3H), 0.79 (s, 3H).

Example 62N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzyl}piperazin-1-yl)benzamideExample 62A ethyl 4-(4-(2-bromobenzyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared using methods described by Bruncko, et. al.,J. Med. Chem. 2007, 50, 641-662.

Example 62B ethyl4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)benzoate

A solution of tris(dibenzylideneacetone)dipalladium(0) (0.284 g) andtricyclohexylphosphine (0.417 g) in dioxane (75 mL) was stirred at roomtemperature for 30 minutes. EXAMPLE 62A (5 g),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.46 g) andpotassium acetate (1.825 g) were added, and the reaction was heated to85° C. for 36 hours. The reaction mixture was diluted with ethyl acetateand washed thoroughly with water and with brine. The combined organiclayers were dried over MgSO₄, filtered and concentrated under vacuum.The crude solid was washed with hexanes and with hexanes/ether (2:1) toobtain the title compound.

Example 62C4-(4-(2-(5-(4-phenylthiazol-2-yl)thiophen-2-yl)benzyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 62B for EXAMPLE40A and 2-(5-bromothiophen-2-yl)-4-phenylthiazole for8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane hydrochloridein EXAMPLE 40B.

Example 62DN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 62C for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.79 (s, 1H), 8.64 (s, 1H),8.59 (s, 1H), 8.06 (br s, 1H), 7.99 (d, 1H), 7.83 (d, 2H), 7.60 (d, 2H),7.50 (m, 3H), 7.36 (d, 1H), 7.11 (m, 3H), 7.01 (m, 4H), 6.97 (d, 1H),3.71 (m, 2H), 3.60 (m, 4H), 3.45 (m, 4H), 3.02 (m, 2H), 2.60 (m, 4H),1.83 (m, 1H), 1.56 (m, 4H).

Example 634-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.04 (s, 1H), 8.66 (t,1H), 8.63 (d, 1H), 7.93 (dd, 1H), 7.75 (d, 3H), 7.63 (d, 1H), 7.57 (s,3H), 7.29 (d, 1H), 7.20-7.26 (m, 2H), 6.95 (d, 2H), 4.56 (s, 1H),3.78-3.89 (m, 2H), 3.31-3.37 (m, 6H), 3.26 (dd, 4H), 2.97-3.18 (m, 2H),2.04 (s, 3H), 1.93 (s, 3H), 1.93 (s, 3H), 1.57-1.80 (m, 10H), 1.21-1.40(m, 5H). MS (ESI) m/e 891 (M−H)⁻.

Example 645-{2-[(4-{4-[({3-nitro-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-(2-phenyl-1,3-benzoxazol-5-yl)-2-furamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.09 (s, 1H), 10.46 (s,1H), 9.27 (s, 1H), 8.59-8.70 (m, 2H), 8.29 (d, 1H), 8.22 (dd, 2H), 8.02(d, 1H), 7.94 (dd, 1H), 7.75-7.84 (m, 3H), 7.59-7.73 (m, 7H), 7.50-7.57(m, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 7.05 (d, 2H), 4.71 (s, 1H), 4.14(s, 1H), 3.72-3.90 (m, 3H), 3.20-3.32 (m, 4H), 1.83-1.97 (m, 1H), 1.61(d, 2H), 1.16-1.33 (m, 3H). MS (ESI) m/e 894 (M−H)⁻.

Example 65N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(triphenylvinyl)benzyl]piperazin-1-yl}benzamideExample 65A 4-(4-(2-(1,2,2-triphenylvinyl)benzyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 62B for EXAMPLE40A and bromotriphenylethylene for8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane hydrochloridein EXAMPLE 40B.

Example 65BN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{-4-[2-(triphenylvinyl)benzyl]piperazin-1-yl}benzamide

The title compound was prepared by substituting EXAMPLE 65A for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.97 (s, 1H), 8.63 (s, 1H),8.07 (br s, 1H), 7.99 (d, 1H), 7.60 (d, 2H), 7.42 (m, 6H), 7.30 (m, 4H),7.26 (m, 6H), 7.07 (m, 2H), 6.99 (m, 4H), 3.82 (br s, 2H), 3.60 (m, 4H),3.45 (m, 4H), 3.02 (m, 2H), 2.62 (m, 4H), 1.83 (m, 1H), 1.56 (m, 4H).

Example 664-{4-[2-(5-methyl-5,6-dihydrophenanthridin-6-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting2-(5-methyl-5,6-dihydro-phenanthridin-6-yl)-benzaldehyde for EXAMPLE 23Ein EXAMPLE 23F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.03 (br s,1H), 8.57 (d, 1H), 8.53 (t, 1H), 7.92 (dd, 1H), 7.90 (d, 2H), 7.83 (dd,1H), 7.76 (d, 2H), 7.41 (d, 1H), 7.28-6.99 (m, 6H), 6.92 (d, 2H), 6.77(td, 1H), 6.59 (dd, 1H), 6.13 (s, 1H), 3.91 (d, 1H), 3.85 (dd, 2H), 3.65(d, 1H), 3.30-3.23 (m, 2H), 2.78 (s, 3H), 2.70-2.53 (m, 5H), 1.91 (s,3H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.38-1.20 (m, 6H), 0.86 (m, 2H).

Example 67N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazin-1-yl}benzamide

The title compound was prepared by substituting (2-formylphenyl)boronicacid pinacol ester for EXAMPLE 23E in EXAMPLE 23F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.94 (br s, 1H), 8.60 (d, 1H), 7.94-7.89 (m,1H), 7.75 (d, 2H), 7.62 (m, 1H), 7.50-7.21 (m, 4H), 7.25 (d, 1H), 6.92(d, 2H), 3.84 (dd, 2H), 3.36-3.32 (m, 8H), 2.51 (br s, 2H), 1.91 (s,3H), 1.62 (dt, 2H), 1.30 (br s, 9H), 1.26 (dd, 2H), 1.16 (s, 6H), 1.07(s, 2H).

Example 684-(4-{2-[2-(2,6-dimethoxybenzoyl)-3-thienyl]benzylidene}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 68A methyl4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)piperidin-1-yl)benzoate

EXAMPLE 61B (259 mg), bis(pinacolato)diboron (206 mg),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (22 mg), and potassium acetate (159 mg) were combined indimethylsulfoxide (2.7 mL). The reaction mixture was heated at 90° C.for 36 hours. The reaction mixture was diluted with ethyl acetate,washed thoroughly with water and with brine, dried over MgSO₄, filteredand concentrated under vacuum. The crude solid was washed with hexanesand with hexanes/ether (2:1) to obtain the title compound.

Example 68B ethyl4-(4-(2-(2-(2,6-dimethoxybenzoyl)thiophen-3-yl)benzylidene)piperidin-1-yl)benzoate

EXAMPLE 68A (0.043 g),(3-bromothiophen-2-yl)(2,6-dimethoxyphenyl)methanone (0.03114 g),tetrakis(triphenylphosphine)palladium(0) (11.00 mg) and cesium fluoride(0.043 g) were combined in 1,2-dimethoxyethane (0.333 ml) and ethanol(0.143 ml). The reaction was heated to 90° C. for 2 hours. The reactionmixture was diluted with ethyl acetate, poured into water, and washedthoroughly with water and with brine. The combined organic layers weredried over MgSO₄, filtered, and concentrated under vacuum. The crudematerial was purified by flash chromatography, eluting with a gradientof 1% methanol/dichloromethane to 5% methanol/dichloromethane.

Example 68C4-(4-(2-(2-(2,6-dimethoxybenzoyl)thiophen-3-yl)benzylidene)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 68B for EXAMPLE50A in EXAMPLE 50B.

Example 68D4-(4-{2-[2-(2,6-dimethoxybenzoyl)-3-thienyl]benzylidene}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 68C for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.95 (s, 1H), 8.63 (m, 2H),7.93 (dd, 1H), 7.87 (d, 1H), 7.72 (d, 2H), 7.27 (d, 1H), 7.20 (s, 1H),7.09 (m, 3H), 6.93 (m, 4H), 6.40 (d, 2H), 5.99 (s, 1H), 3.83 (dd, 2H),3.60 (s, 6H), 3.26 (m, 6H), 2.31 (m, 2H), 2.22 (m, 2H), 1.90 (br s, 1H),1.60 (m, 2H), 1.26 (m, 4H).

Example 691-[adamantan-1-yl]-4-{2-[(1-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperidin-4-ylidene)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamideExample 69A4-{4-[2-(1-adamantan-1-yl-3-diphenylcarbamoyl-1H-pyrazol-4-yl)-benzylidene]-piperidin-1-yl}-benzoicacid ethyl ester

The title compound was prepared by substituting1-adamantan-1-yl-4-bromo-1H-pyrazole-3-carboxylic acid diphenylamide for(3-bromothiophen-2-yl)(2,6-dimethoxyphenyl)methanone in EXAMPLE 68B.

Example 69B4-{4-[2-(1-adamantan-1-yl-3-diphenylcarbamoyl-1H-pyrazol-4-yl)-benzylidene]-piperidin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 69A for EXAMPLE50A in EXAMPLE 50B.

Example 69C1-[adamantan-1-yl]-4-{2-[(1-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperidin-4-ylidene)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide

The title compound was prepared by substituting EXAMPLE 69B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.95 (s, 1H), 8.64 (m, 2H),7.93 (dd, 1H), 7.43 (d, 2H), 7.52 (s, 1H), 7.26 (m, 4H), 7.19 (m, 4H),7.13 (m, 3H), 6.91 (m, 6H), 5.58 (s, 1H), 3.83 (dd, 2H), 3.47 (t, 2H),3.25 (m, 6H), 2.23 (m, 4H), 2.07 (m, 3H), 1.89 (m, 6H), 1.62 (m, 8H),1.26 (m, 3H).

Example 70N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzamideExample 70A ethyl4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzoate

EXAMPLE 16C (60 mg), 3-phenylpropanoyl chloride (22 mg) anddiisopropylethylamine (0.05 mL) were dissolved in anhydrousdichloromethane (3 mL). The reaction mixture was stirred at roomtemperature overnight. The reaction was quenched with saturated NaHCO₃aqueous solution, and extracted with ethyl acetate. The organic phasewas washed with water, brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column purification with0-5% methanol in dichloromethane to afford the title compound.

Example 70B4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 70A for EXAMPLE2A in EXAMPLE 2B.

Example 70CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 70B for EXAMPLEl A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE1B. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.03 (m, 1H), 8.64 (m,2H), 7.93 (dd, 1H), 7.76 (d, 2H), 7.58 (s, 1H), 7.39 (m, 2H), 7.28 (d,1H), 7.18 (m, 3H), 7.00 (m, 5H), 4.32 (m, 1H), 3.83 (m, 2H), 3.26 (m,8H), 2.81 (m, 6H), 2.19 (m, 2H), 1.90 (m, 4H), 1.67 (m, 7H), 1.22 (m,11H).

Example 714-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 71A ethyl4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzylidene)piperidin-1-yl)benzoate

The title compound was prepared by substituting8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane hydrochloridefor (3-bromothiophen-2-yl)(2,6-dimethoxyphenyl)methanone in EXAMPLE 68B.

Example 71B4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzylidene)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE50A in EXAMPLE 50B.

Example 71C4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-lmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 71B for EXAMPLE1A and EXAMPLE 23A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.54 (s, 1H), 9.36 (br s, 1H),8.48 (d, 1H), 7.76 (dd, 1H), 7.53 (m, 3H), 7.34 (m, 3H), 7.00 (m, 1H),6.84 (d, 2H), 6.81 (dd, 1H), 6.44 (d, 1H), 6.37 (br s, 1H), 4.36 (d,2H), 3.82 (m, 3H), 3.36 (m, 2H), 3.26 (m, 4H), 3.18 (m, 2H), 2.36 (m,3H), 2.23 (m, 4H), 1.90 (m, 3H), 1.81 (m, 2H), 1.62 (m, 5H), 1.40 (m,3H).

Example 72N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamideExample 72A ethyl 4-(4-(4-bromobenzylidene)piperidin-1-yl)benzoate

The title compound was prepared by substituting(4-bromobenzyl)triphenylphosphonium bromide for(2-bromobenzyl)triphenylphosphonium bromide in EXAMPLE 61B.

Example 72B ethyl4-(4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzylidene)piperidin-1-yl)benzoate

EXAMPLE 72A (40 mg),(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (100 μl),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (9.2 mg,), palladium(II)acetate (2.4 mg), and sodium tert-butoxide (14 mg) were added to toluene(0.2 mL), the reaction was purged with nitrogen and heated at 100° C.overnight. The reaction was cooled, then diluted with water andextracted with ethyl acetate. The organic layer was washed with brineand dried over sodium sulfate. After filtration and concentration, thecrude material was purified by column chromatography on silica gel using94/6 hexanes/ethyl acetate.

Example 72C4-(4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzylidene)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 72B for EXAMPLE8D in EXAMPLE 8E.

Example 72DN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide

The title compound was prepared by substituting EXAMPLE 72C for EXAMPLE8E and EXAMPLE 23A for EXAMPLE 2D in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.97 (br s, 1H), 8.65 (t, 1H), 8.63 (d, 1H),7.95 (dd, 1H), 7.76 (d, 2H), 7.28 (d, 1H), 7.06 (br s, 2H), 6.95 (d,2H), 6.90 (v br s, 2H), 6.26 (s, 1H), 3.85 (m, 2H), 3.50 (m, 5H), 3.33(t, 2H), 3.25 (m, 2H), 2.38 (m, 3H), 2.00 (m, 1H), 1.94 (m, 2H), 1.80(m, 1H), 1.60 (m, 3H), 1.25 (m, 5H), 1.21 (s, 3H), 1.09 (d, 1H), 1.00(s, 6H).

Example 73N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamideExample 73A ethyl 4-(4-(3-bromobenzylidene)piperidin-1-yl)benzoate

The title compound was prepared by substituting(3-bromobenzyl)triphenylphosphonium bromide for(2-bromobenzyl)triphenylphosphonium bromide in EXAMPLE 61B.

Example 73B ethyl4-(4-(3-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzylidene)piperidin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 73A for EXAMPLE72A in EXAMPLE 72B.

Example 73C4-(4-(3-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)benzylidene)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 73B for EXAMPLE8D in EXAMPLE 8E.

Example 73DN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide

The title compound was prepared by substituting EXAMPLE 73C for EXAMPLE8E and EXAMPLE 23A for EXAMPLE 2D in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.00 (br s, 1H), 8.68 (t, 1H), 8.63 (d, 1H),7.95 (dd, 1H), 7.76 (d, 2H), 7.30 (d, 1H), 7.18 (v br s, 2H), 6.96 (d,2H), 6.75 (v br s, 2H), 6.26 (s, 1H), 3.85 (m, 2H), 3.50 (m, 5H), 3.37(t, 2H), 3.25 (m, 2H), 2.40 (m, 2H), 2.37 (m, 1H), 2.00 (m, 1H), 1.94(m, 2H), 1.80 (m, 1H), 1.60 (m, 3H), 1.25 (m, 5H), 1.20 (s, 3H), 1.12(d, 1H), 1.00 (s, 6H).

Example 744-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.96 (s, 1H), 8.59-8.72(m, 2H), 7.93 (dd, 1H), 7.72 (d, 2H), 7.64 (dd, 1H), 7.54 (d, 1H),7.22-7.40 (m, 4H), 7.16 (s, 1H), 6.94 (d, 2H), 6.43 (s, 1H), 3.83 (dd,2H), 3.53-3.62 (m, 2H), 3.37-3.43 (m, 4H), 3.19-3.29 (m, 2H), 2.40-2.46(m, 2H), 2.28-2.36 (m, 2H), 1.97 (s, 2H), 1.83-1.93 (m, 5H), 1.55-1.70(m, 6H), 1.18-1.31 (m, 2H). MS (ESI) m/e 888 (M−H).

Example 75N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzylidene}piperidin-1-yl)benzamide

¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.97 (s, 1H), 8.58-8.71(m, 2H), 8.08 (s, 1H), 7.89-7.98 (m, 3H), 7.88-7.98 (m, 3H), 7.74 (d,2H), 7.63-7.71 (m, 2H), 7.24-7.46 (m, 8H), 6.97 (d, 2H), 6.47 (s, 1H),3.83 (dd, 2H), 3.57-3.67 (m, 2H), 3.38-3.46 (m, 2H), 3.33-3.37 (m, 2H),3.19-3.29 (m, 4H), 2.40-2.48 (m, 2H), 2.29-2.37 (m, 2H), 1.82-1.98 (m,1H), 1.61 (d, 2H), 1.16-1.32 (m, 2H). MS (ESI) m/e 830 (M−H)⁻.

Example 76N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-oxo-4H-chromen-6-yl)benzamideExample 76A 4-(4-oxo-4H-chromen-6-yl)benzoic acid

The title compound was prepared as described in EXAMPLE 4A using4-boronobenzoic acid in place of 4-(methoxycarbonyl)phenylboronic acidand 6-bromo-4H-chromen-4-one in place of 1-bromo-3-iodobenzene.

Example 76BN-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-oxo-4H-chromen-6-yl)benzamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE76A in place of EXAMPLE 1A and4-[(adamantan-1-ylmethyl)amino]-3-nitrobenzenesulfonamide in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.95 (s, 1H), 8.52 (d, 1H), 8.40 (t, 1H), 8.33(d, 1H), 8.25 (d, 1H), 8.15 (d, 1H), 8.00 (d, 2H), 7.89 (d, 1H), 7.73(m, 2H), 7.16 (d, 1H), 6.40 (d, 1H), 4.03 (m, 1H), 3.13 (d, 2H), 1.99(m, 3H), 1.65 (m, 3H), 1.58 (s, 6H).

Example 77N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(1-octyl-1H-pyrazol-4-yl)benzamideExample 77A 4-iodo-1-octyl-1H-pyrazole

To a slurry of NaH (60% in mineral oil, 271 mg, 6.77 mmol) inN,N-dimethylformamide (20 mL) was added 4-iodo-1H-pyrazole (1.25 g, 6.44mmol), and the reaction was stirred for 30 minutes. 1-Octyl bromide(1.22 mL, 7.08 mmol) was then added and the reaction stirred for 24hours. The mixture was poured into water (200 mL), and the resultingsolution was extracted three times with ether. The combined etherextracts were washed three times with water and brine, dried overNa₂SO₄, filtered, and concentrated to give the title compound.

Example 77B 4-(1-octyl-1H-pyrazol-4-yl)benzoic acid

The title compound was prepared as described in EXAMPLE 4A using4-boronobenzoic acid in place of 4-(methoxycarbonyl)phenylboronic acidand EXAMPLE 77A in place of 1-bromo-3-iodobenzene.

Example 77CN-[(4-[adamantan-1-ylmethyl]amino-3-nitrophenypsulfonyl]-4-(1-octyl-1H-pyrazol-4-yl)benzamide

The title compound was prepared as described in EXAMPLE 1B using EXAMPLE77B in place of EXAMPLE 1A and4-[(adamantan-1-ylmethyl)amino]-3-nitrobenzenesulfonamide in place of4-chloro-3-nitrobenzenesulfonamide. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.95 (s, 1H), 8.55 (d, 1H), 8.43 (t, 1H), 8.23(s, 1H), 7.90 (m, 3H), 7.55 (d, 2H), 7.19 (d, 1H), 4.03 (m, 1H), 3.14(d, 2H), 1.97 (m, 3H), 1.78 (t, 2H), 1.65 (m, 5H), 1.58 (s, 6H), 1.23(br s, 10H), 0.84 (t, 3H).

Example 784-[5-(4-{[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenyl)-1,3-benzothiazol-2-yl]butanoicacid Example 78A4-[(adamantan-1-ylmethyl)-amino]-3-nitro-benzenesulfonamide

The title compound was prepared by substituting 1-adamantanemethylaminefor cyclohexylmethylamine in EXAMPLE 2D.

Example 78B 4-(5-Bromo-benzothiazol-2-yl)-butyric acid methyl ester

5-Bromo-2-methylbenzothiazole (1000 mg) was dissolved in tetrahydrofuran(25 mL) and the mixture was cooled to −78° C. using an isopropanol/dryice bath. Lithium diisopropylamide (1.5M in cyclohexane, 4.40 mL) wasadded, and the solution stirred for 30 minutes at −78° C. Methyl3-bromopropionate (1.20 mL, 1836 mg) was added and the solution stirredat −78° C. for two hours. The reaction was quenched with 1M aqueoushydrochloric acid, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by flash column chromatography on silica gel using 10% ethylacetate hexanes.

Example 78C 4-[2-(3-Ethoxycarbonyl-propyl)-benzothiazol-5-yl]-benzoicacid

EXAMPLE 78B (275 mg), 4-carboxyphenylboronic acid (160 mg), sodiumcarbonate (2M aqueous, 1.1 mL), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (65 mg) were added to dimethylformamide (1.5 mL),ethanol (1.5 mL), and water (0.5 mL) which had been degassed and flushedwith nitrogen three times. The solution was heated to 90° C. and stirredfor 16 hours. The solution was cooled, added to water, extracted withethyl acetate, washed with brine, dried on anhydrous sodium sulfate,filtered, concentrated, and purified by flash column chromatography onsilica gel using 5% methanol in ethyl acetate to obtain the ethyl esterproduct via transesterification with the ethanol solvent.

Example 78D4-[5-(4-{4-[(adamantan-1-ylmethyl)-amino]-3-nitro-benzenesulfonylaminocarbonyl}-phenyl)-benzothiazol-2-yl]-butyricacid ethyl ester

The title compound was prepared by substituting EXAMPLE 78C for EXAMPLE1A and EXAMPLE 78A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.

Example 78E4-[5-(4-{[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenyl)-1,3-benzothiazol-2-yl]-butanoicacid

The title compound was prepared by substituting EXAMPLE 78D for EXAMPLE2A in EXAMPLE 2B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.52 (br s,1H), 12.13 (br s, 1H), 8.68 (d, 1H), 8.59 (t, 1H), 8.31 (d, 1H), 8.17(d, 1H), 8.00-7.91 (m, 5H), 7.78 (dd, 1H), 7.38 (d, 1H), 3.22-3.13 (m,4H), 2.39 (t, 2H), 2.05 (m, 2H), 1.97 (br s, 4H), 2.66 (m, 4H), 1.58 (brs, 6H), 0.86 (m, 1H).

Example 79N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-[(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]oct-3-yl]benzamideExample 79A ethyl4-((1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octan-3-yl)benzoate

The title compound was prepared by substituting(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane for benzyl2,6-diazabicyclo[3.2.1]octane-6-carboxylate in EXAMPLE 8A.

Example 79B4-41R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octan-3-yl)benzoic acid

The title compound was prepared by substituting EXAMPLE 79A for EXAMPLE8D in EXAMPLE 8E.

Example 79CN-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-[(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]oct-3-yl]benzamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 79B for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.99 (br s, 1H), 8.63 (d, 1H), 8.28 (d, 1H),7.95 (dd, 1H), 7.74 (d, 2H), 7.39 (d, 1H), 6.80 (d, 2H), 3.95 (m, 1H),3.88 (m, 2H), 3.47 (m, 2H), 3.40 (d, 1H), 3.22 (d, 1H), 3.18 (d, 1H),2.84 (d, 1H), 1.90 (m, 4H), 1.62 (m, 4H), 1.40 (m, 1H), 0.92 (s, 3H),0.90 (s, 6H).

Example 80 6-{3-[adamantan-1-yl]-4-methoxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide

The title compound was prepared by substituting6-(3-adaman-1-yl-4-methoxy-phenyl)-naphthalene-2-carboxylic acid forEXAMPLE 1A and EXAMPLE 2D for 4-chloro-3-nitrobenzenesulfonamide inEXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.57 (br s, 1H),8.70 (d, 1H), 8.65 (t, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.10 (d, 1H),8.06 (d, 1H), 8.00 (dd, 1H), 7.88 (m, 2H), 7.66 (dd, 1H), 7.58 (d, 1H),7.28 (d, 1H), 7.13 (d, 1H), 3.87 (s, 3H), 2.63 (br s, 6H), 2.07 (br s,4H), 1.78-1.62 (m, 12H), 1.26-1.15 (m, 4H), 1.01 (t, 2H).

Example 814-{4-[adamantan-1-ylacetyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 81A 4-[4-(adamantan-1-ylacetyl)piperazin-1-yl]benzoic acid

The title compound was prepared by substituting EXAMPLE 58A for EXAMPLE8D in EXAMPLE 8E.

Example 81B4-{4-[adamantan-1-ylacetyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 81A for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.05 (br s, 1H), 8.64 (d, 1H), 8.30 (d, 1H),7.95 (dd, 1H), 7.76 (d, 2H), 7.40 (d, 1H), 6.95 (d, 2H), 3.94 (m, 1H),3.87 (m, 2H), 3.60 (m, 4H), 3.45 (m, 2H), 3.29 (m, 4H), 2.15 (s, 2H),1.90 (m, 5H), 1.60 (m, 14H).

Example 824-{[adamantan-1-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 82A ethyl 4-{[adamantan-1-ylmethyl]amino}benzoate

The title compound was prepared by substituting 1-adamantanemethylaminefor (2-adamantylmethyl)amine hydrochloride in EXAMPLE 50A.

Example 82B 4-{[adamantan-1-ylmethyl]amino}benzoic acid

The title compound was prepared by substituting EXAMPLE 82A for EXAMPLE50A in EXAMPLE 50B.

Example 82C4-{[adamantan-1-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 82B for EXAMPLE1A and EXAMPLE 41A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.

Example 83N-{1-[4-({[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}carbamoyl)phenyl]piperidin-4-yl}adamantane-1-carboxamideExample 83A ethyl 4-(4-(tert-butoxycarbonylamino)piperidin-1-yl)benzoate

The title compound was prepared by substituting tert-butylpiperidin-4-ylcarbamate for benzyl2,6-diazabicyclo[3.2.1]octane-6-carboxylate in EXAMPLE 8A.

Example 83B ethyl 4-(4-aminopiperidin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 83A for EXAMPLE11A in EXAMPLE 11B.

Example 83C ethyl4-{4-[(adamantan-1-ylcarbonyl)amino]piperidin-1-yl}benzoate

The title compound was prepared by substituting EXAMPLE 83B for EXAMPLE8B in EXAMPLE 8C.

Example 83D 4-{4-[(adamantan-1-ylcarbonyl)amino]piperidin-1-yl}benzoicacid

The title compound was prepared by substituting EXAMPLE 83C for EXAMPLE8D in EXAMPLE 8E.

Example 83EN-{1-[4-({[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}carbamoyl)phenyl]piperidin-4-yl}adamantane-1-carboxamide

The title compound was prepared by substituting EXAMPLE 41A for EXAMPLE2D and EXAMPLE 83D for EXAMPLE 8E in EXAMPLE 8F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.00 (br s, 1H), 8.64 (d, 1H), 8.30 (d, 1H),7.95 (dd, 1H), 7.76 (d, 2H), 7.39 (d, 1H), 7.10 (d, 1H), 6.92 (d, 2H),3.90 (m, 6H), 3.45 (m, 2H), 2.92 (m, 2H), 1.90 (br s, 6H), 1.70 (m,15H), 1.45 (m, 2H).

Example 844-[adamantan-2-ylamine]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamideExample 84A ethyl 4-[adamantan-2-ylamino]benzoate

The title compound was prepared by substituting 2-adamantanaminehydrochloride for (2-adamantylmethyl)amine hydrochloride in EXAMPLE 50A.

Example 84B 4-[adamantan-2-ylamino]benzoic acid

The title compound was prepared by substituting EXAMPLE 84A for EXAMPLE50A in EXAMPLE 50B.

Example 84C4-[adamantan-2-ylamino]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 84B for EXAMPLE1A and EXAMPLE 41A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.82 (s, 1H), 8.63 (d, 1H),8.29 (d, 1H), 7.94 (dd, 1H), 7.61 (d, 2H), 7.38 (d, 1H), 6.64 (d, 2H),3.95 (m, 1H), 3.88 (m, 2H), 3.36 (m, 1H), 3.47 (m, 2H), 2.01 (m, 2H),1.92 (m, 4H), 1.83 (m, 6H), 1.70 (m, 4H), 1.50 (m, 2H).

Example 85N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}benzamideExample 85A ethyl4-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yloxy)benzoate

Ethyl 4-iodobenzoate (276 mg),(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol (154 mg),1,10-phenanthroline (36 mg), copper iodide (19 mg) and cesium carbonate(652 mg) were combined in toluene (0.5 mL). The reaction was heated to120° C. over 36 hours. The reaction mixture was removed from heat,allowed to cool, diluted with ethyl acetate and poured into water. Theorganic layer was washed thoroughly with water and brine, dried overMgSO₄, filtered and concentrated under vacuum. The crude material waspurified by flash chromatography eluting with 95/5 hexanes/ether.

Example 85B4-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 85A for EXAMPLE50A in EXAMPLE 50B.

Example 85CN-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}benzamide

The title compound was prepared by substituting EXAMPLE 85B for EXAMPLE1A and EXAMPLE 41A for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 12.26 (br s, 1H), 8.66 (d, 1H),8.30 (d, 1H), 7.95 (dd, 1H), 7.82 (d, 2H), 7.40 (d, 1H), 7.03 (d, 2H),4.67 (m, 1H), 3.96 (m, 1H), 3.88 (m, 2H), 3.47 (m, 3H), 2.65 (m, 1H),2.36 (m, 1H), 2.25 (m, 1H), 1.93 (m, 3H), 1.85 (m, 1H), 1.64 (m, 3H),1.23 (s, 3H), 1.10 (d, 3H), 0.99 (s, 3H).

1.-2. (canceled)
 3. A method of treating bladder cancer, brain cancer,breast cancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of Tcell or B cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non small cell lung cancer, chronic lymphocyticleukemia, myeloma, prostate cancer, small cell lung cancer or spleencancer in a patient, said method comprising administering to the patienta therapeutically effective amount of a compound, or a therapeuticallyacceptable salt thereof, wherein the compound is selected from the groupconsisting of:4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}phenyl)sulfonyl]benzamide;4-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{benzoyl[1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(phenylacetyl)[(1S,2S3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-4-(4-{3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[(1R,5R)-3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzamide;4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(1-methyl-2-oxo-3-azabicyclo[3.1.1]hept-3-yl)phenyl]sulfonyl}benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]hept-2-yl]amino}benzyl)piperazin-1-yl]benzamide;4-[4-(2-{[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[(1R,5R)-2-(4-chlorophenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{4-[(2-{[adamantan-2-ylmethyl]amino}-5,5-dimethylcyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[(5,5-dimethyl-2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}cyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)-5-nitrobenzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{2-[2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;1-[adamantan-1-yl]-4-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;4-(4-{2-[2-(adamantan-1-yl)-6-methylimidazo[1,2-a]pyridin-8-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-(adamantan-2-yl)-6-methyl-8-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}imidazo[1,2-a]pyridine-2-carboxamide;4-(4-{2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;N-cyclooctyl-5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-2-furamide;N-benzyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzyl)piperazin-1-yl]benzamide;4-(4-{2-[3-azabicyclo[3.2.2]non-3-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[tricyclo[4.3.1.13,8]undec-4-en-4-yl]benzyl}piperazin-1-yl)benzamide;7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-phenylbicyclo[2.2.1]hept-2-ene-1-carboxamide;7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]bicyclo[2.2.1]hept-2-ene-1-carboxamide;N-(adamantan-1-ylmethyl)-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;N-cyclopropyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxylic;4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{4-[adamantan-2-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{1S,5S)-3-[adamantan-1-ylcarbonyl]-3,6-diazabicyclo[3.2.0]hept-6-yl}-N-{[3-nitro-4-tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;N-{[3-nitro-4-(tetrahyrdo-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({-4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;6-{3-[adamantan-1-yl]-4-hydroxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{[adamantan-2-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{2-[adamantan-1-yl]ethoxy}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;N3-[adamantan-1-ylacetyl]-N3-benzyl-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-beta-alaninamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamide;4-{4-[adamantan-1-yl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[3,5-dimethyladamantan-1-yl]piperazin-1-yl}benzamide;[(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b4′,5′-d]pyran-3a-yl]methyl;4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;4-(4-{2-[adamantan-1-yl]ethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-({(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)biphenyl-4-carboxamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidine-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzyl}piperazin-1-yl)benzamide;4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-(2-phenyl-1,3-benzoxazol-5-yl)-2-furamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{-[2-(triphenylvinyl)benzyl]piperazin-1-yl}benzamide;4-{4-[2-(5-methyl-5,6-dihydrophenanthridin-6-yl)benzyl]piperazin-1-yl}-N-E{3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazin-1-yl}benzamide;4-(4-{2-[2-(2,6-dimethoxybenzoyl)-3-thienyl]benzylidene}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;1-[adamantan-1-yl]-4-{2-[(1-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperidin-4-ylidene)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzamide;4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzylidene}piperidin-1-yl)benzamide;N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-oxo-4H-chromen-6-yl)benzamide;N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(1-octyl-1H-pyrazol-4-yl)benzamide;4-[5-(4-{[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl}carbamoyl]phenyl)-1,3-benzothiazol-2-yl]butanoic;N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-[(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]oct-3-yl]benzamide;6-{3-[adamantan-1-yl]-4-methoxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;4-{4-[adamantan-1-ylacetyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{[adamantan-1-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;N-{1-[4-({[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}carbamoyl)phenyl]piperidin-4-yl}adamantane-1-carboxamide;4-[adamantan-2-ylamino]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;andN-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}benzamide.4. A method of treating bladder cancer, brain cancer, breast cancer,bone marrow cancer, cervical cancer, chronic lymphocytic leukemia,colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of Tcell or B cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non small cell lung cancer, chronic lymphocyticleukemia, myeloma, prostate cancer, small cell lung cancer or spleencancer in a patient, said method comprising administering to the patienttherapeutically effective amount of a compound, or a therapeuticallyacceptable salt thereof, wherein the compound is selected from the groupconsisting of:4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}phenyl)sulfonyl]benzamide;4-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{benzoyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(phenylacetyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide;4-{6-[adamantan-1-ylmethyl]-2,6-diazabicyclo[3.2.1]oct-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-4-(4-{(3-phenylpropanoyl)[(1S,2S3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-[4-{[(2R)-4-(morpholin-4-yl)-1-(phenylthio)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-{(1S,4S)-5-[adamantan-1-ylmethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[(1R,5R)-3-bromo-5-methyladamantan-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[3,5-dimethyladamantan-1-yl]methyl}piperazin-1-yl)benzamide;4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(1-methyl-2-oxo-3-azabicyclo[3.1.1]hept-3-yl)phenyl]sulfonyl}benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-octahydro-1H-4,7-methanoinden-5-ylamino]benzyl}piperazin-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,4R,6S)-5,5,6-trimethylbicyclo[2.2.1]hept-2-yl]amino}benzyl)piperazin-1-yl]benzamide;4-[4-(2-{[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}-benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[(1R,5R)-2-(4-chlorophenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{4-[(2-{[adamantan-2-ylmethyl]amino}-5,5-dimethylcyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[(5,5-dimethyl-2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}cyclohexyl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)-5-nitrobenzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{2-[2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;1-[adamantan-1-yl]-4-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;4-(4-{2-[2-(adamantan-1-yl)-6-methylimidazo[1,2-a]pyridin-8-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-(adamantan-2-yl)-6-methyl-8-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}imidazo[1,2-a]pyridine-2-carboxamide;4-(4-{2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5,5,6-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzyl}piperazin-1-yl)benzamide;N-cyclooctyl-5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-2-furamide;N-benzyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzyl)piperazin-1-yl]benzamide;4-(4-{2-[3-azabicyclo[3.2.2]non-3-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[tricyclo[4.3.1.13,8]undec-4-en-4-yl]benzyl}piperazin-1-yl)benzamide;7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-phenylbicyclo[2.2.1]hept-2-ene-1-carboxamide;7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]bicyclo[2.2.1]hept-2-ene-1-carboxamide;N-(adamantan-1-ylmethyl)-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;N-cyclopropyl-7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxamide;7,7-dimethyl-2-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}bicyclo[2.2.1]hept-2-ene-1-carboxylic;4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide:4-{4-[adamantan-1-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{4-[adamantan-2-ylcarbonyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{5-[adamantan-1-ylcarbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{1S,5S)-3-[adamantan-1-ylcarbonyl]-3,6-diazabicyclo[3.2.0]hept-6-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;N-{[3-nitro-4-tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-(4-{(3-phenylpropyl)[1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;6-{3-[adamantan-1-yl]-4-hydroxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{[adamantan-2-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{2-[adamantan-1-yl]ethoxy}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;N3-[adamantan-1-ylacetyl]-N3-benzyl-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-beta-alaninamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamide;4-{4-[adamantan-1-yl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4-{4-[3,5-dimethyladamantan-1-yl]piperazin-1-yl}benzamide;[(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b4′,5′-d]pyran-3a-yl]methyl;4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;4-(4-{2-[adamantan-1-yl]ethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{4-[(4′-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-N-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)benzamide;N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-4′-({(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)biphenyl-4-carboxamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidin-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzyl}piperazin-1-yl)benzamide;4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;5-{2-[(4-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl]phenyl}-N-(2-phenyl-1,3-benzoxazol-5-yl)-2-furamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{-4-[2-(triphenylvinyl)benzyl]piperazin-1-yl}benzamide;4-{-[2-(5-methyl-5,6-dihydrophenanthridin-6-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazin-1-yl}benzamide;4-(4-{2-[2-(2,6-dimethoxybenzoyl)-3-thienyl]benzylidene}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;1-[adamantan-1-yl]-4-{2-[(1-{4-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenyl}piperidin-4-ylidene)methyl]phenyl}-N,N-diphenyl-1H-pyrazole-3-carboxamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[octahydro-1H-4,7-methanoinden-5-yl(3-phenylpropanoyl)amino]benzyl}piperazin-1-yl)benzamide;4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}benzylidene)piperidin-1-yl]benzamide;4-[4-(2-{5-[4-(adamantan-1-yl)-1,3-thiazol-2-yl]-2-thienyl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{2-[5-(4-phenyl-1,3-thiazol-2-yl)-2-thienyl]benzylidene}piperidin-1-yl)benzamide:N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-oxo-4H-chromen-6-yl)benzamide;N-[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-4-(1-octyl-1H-pyrazol-4-yl)benzamide;4-[5-(4-{[(4-{[adamantan-1-ylmethyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenyl)-1,3-benzothiazol-2-yl]butanoic;N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-[(1R,5S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]oct-3-yl]benzamide;6-{3-[adamantan-1-yl]-4-methoxyphenyl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-naphthamide;4-{4-[adamantan-1-ylacetyl]piperazin-1-yl}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-{[adamantan-1-ylmethyl]amino}-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;N-{1-[4-({[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}carbamoyl)phenyl]piperidin-4-yl}adamantane-1-carboxamide;4-[adamantan-2-ylamino]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;andN-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}benzamide;and a therapeutically effective amount of one additional therapeuticagent or more than one additional therapeutic agent.